Pro drugs for selective drug delivery

ABSTRACT

A broad class of pharmaceutical agents which react directly with electron carriers or with reactive species produced by electron transport to release a pharmacologically active molecule to effect a therapeutic functional change in the organism by a receptor or nonrecepter mediated action.

This application is a continuation of application Ser. No. 07/446,439filed on Dec. 4, 1989, now U.S. Pat. No. 5,428,163, which in turn is acontinuation-in-part of application Ser. No. 06/948,326 filed on Dec.31, 1986, now abandoned and application Ser. No. 07/175,970 filed Mar.31, 1998, now abandoned. The contents of all of the aforementionedapplications are expressly incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to therapeutic pharmaceutical agents whichare activated intracellularly by reaction with cellular electroncarriers or free radicals to cause release of a free and active drugmolecule.

CROSS REFERENCE TO RELATED APPLICATIONS BACKGROUND OF THE INVENTION

The effects of the preponderance of drugs result from their interactionwith functional macromolecular components of the organism. Suchinteraction alters the function of the pertinent cellular component andthereby initiates the series of biochemical and physiological changesthat are characteristic of the response to the drug. The term receptordenotes the component of the organism with which the chemical agentinteracts. There are fundamental corollaries to the statement that thereceptor for a drug can be any functional macromolecular component ofthe organism. One is that a drug is potentially capable of altering therate at which any bodily function proceeds; a second is that, by virtueof interactions with specific receptors, drugs do not create effects butmerely modulate the rates of ongoing functions. A simple pharmacologicaldictum thus states that a drug cannot impart a new function to a cell.Functional changes due to a drug result from either enhancement orinhibition of the unperturbed rate. Furthermore, a drug that has nodirect action can cause a functional change by competition for a bindingsite with another, active regulatory ligand of the receptor. Drugs aretermed agonists when they cause effects as a result of direct alterationof the fundamental properties of the receptor with which they interact.Compounds that are themselves devoid of intrinsic pharmacologicalactivity but cause effects by inhibition of the action of a specificagonist (eg. by competition for agonist binding sites) are designated asantagonists.

At least from a numerical standpoint, the proteins of the cell form themost important class of drug receptors. Obvious examples are the enzymesof crucial metabolic or regulatory pathways (eg., tyrosine hydroxylase;3-hydroxy-3-methylglutaryl-CoA reductase), but of equal interest areproteins involved in transport processes (eg. Ca²⁺ -ATPase; Na⁺ -K⁺-ATPase) or those that are protein kinases which activate other proteinsas a consequence of their binding a secondary messenger such as cAMP.Specific binding properties of other cellular constituents can beexploited. Thus, nucleic acids are important drug receptors,particularly for chemotherapeutic approaches to the control ofmalignancy, and plant lectins shown remarkable specificity forrecognition of specific carbohydrate residues in polysaccharides andglycoproteins. Small ions such as Ca²⁺ which can function as aregulatory ion or Fe²⁺ which can serve as an essential enazmaticcofactor can be exploited as drug receptors. And, drugs can also producea functional change by a nonreceptor-mediated action. Certain drugs thatare structural analogues of normal biological constituents may beincorporated into cellular components and thereby alter their function.This has been termed a "counterfeit incorporation mechanism" and hasbeen implemented with analogues of purines and pyrimidines that can beincorporated into nucleir acids and that have utility in cancerchemotherapy and that have antiviral activity. Also, specificconstituents of pathogens can be exploited as receptors. For example,the electron carriers of bacterial can serve as receptors as describedin my previous U.S. patent application Ser. No. 948,326, and thereplicative enzymes of viruses can be serve as receptors as describedbelow for the virus HIV. Many compounds are known which have receptor ornonreceptor mediated in vitro activity as appears in Handbook of EnzymeInhibitors, Mahendra Kumor Jain, 1982, Wiley Interscience, New York,hereby incorporated by reference. However, only a small percentageproduce the desired functional change in vivo or have a high therapeuticratio because they are toxic in their free form; they are rapidlyinactivated or excreted; or, they cannot obtain access to their targetreceptor or site of action because they are impermeant to cells orbiological barriers such as the blood brain barrier due to unfavorableenergetics due, for example, to the possession of polar or chargegroups; or, they are toxic as a consequence of being nonselective withregards to their access to and action with receptors in one biologicalenvironment or compartment relative to another. In these cases,compounds which demonstrate in vitro efficacy are ineffectivetherapeutics.

SUMMARY OF THE INVENTION

A broad class of pharmaceutical agents is disclosed herein as theLuminide class of pharmaceuicals. Luminide agents are three part or fourpart molecules where each part is a functionality with a definedpurpose. Exemplary Luminides are A-B-C , D-A-B-C, A-D-B-C, and ##STR1##where A represents a functionality which is activatable by theenvironment and capable of transferring energy from its own excitedstate to the B functionality which is an energy acceptor. Upon receivingenergy from A, B achieves an excited state which relaxes through theheterolytic cleavage of the covalent bond of B with C where C is a drugmoiety which is released into the intracellular compartment whereactivation of A occured. Released C can act locally or at a distantsite. D serves as an electron transfer functionality which gains (loses)electrons from (to) the environment and donates (accepts) electrons to(from) A to activate it so that the energy of excited A is transferredto B with release of C as occurs for the three functionality case.

In both cases, free C is a drug molecule. The released drug moleculeeffects a therapeutic functional change by a mechanism which comprisesreceptor mediated mechanisms including reversible or irreversiblecompetitve agonism or antagonism including a suicide substrate ortransition state analogue mechanism or a noncompetitive or uncompetitveagonism or antagonism or the action is by a nonreceptor mediatedmechanism including a "counterfeit incorporation mechanism".

The chemical and physical properties of the Luminide agents such aspermeance and reactivity to different oxidoreductase enzymes, electroncarriers, or different free radicals including those of oxygen areexploited to control the environment into which C is released. Permeanceof the Luminide agent to the blood brain barrier or cell membranes, oraffinity of the Luminide agent to plasma proteins which results in adecreased excretion rate relative to free C, or lack of reactivity ofextracellular enzymes with the Luminide agent relative to free C areexemplary mechanism where by Luminides provide for the release of activefree C in the proper biological compartment or in the presence of thetarget receptor so that the desired therapeutic- change is achieved.Thus, Luminides serve as therapeutic drugs. And, the present invention,Luminides, a broad class of pharmaceutical agents comprisesantilipidemic drugs, anticholesterol drugs, contraceptive agents,anticoagulants, anti-inflamatory agents, immuno-suppressive drugs,antiarrhythmic agents, antineoplastic drugs, antihypertensive drugs,epinephrine blocking agents, cardiac inotropic drugs, antidepressantdrugs, diuretics, antifungal agents, antibacterial drugs, anxiolyticagents, sedatives, muscle relaxants, anticonvulsants, agents for thetreatment of ulcer disease, agents for the treatment of asthma andhypersensitivity reactions, antithroboembolic agents, agents for thetreatment of muscular dystrophy, agents to effect a therapeuticabortion, agents for the treatment of anemia, agents to improveallograft survival, agents for the treatment of disorders of purinemetabolism, agents for the treatment of ischemic heart disease, agentsfor the treatment of opiate withdrawal, agents which activate theeffects of secondary messenger inositol triphosphate, agents to blockspinal reflexes, and antiviral agents including a drug for the treatmentof AIDS.

DETAILED DESCRIPTION OF THE INVENTION

Electron transferring and transporting elements are ubiquitous and arenecessary for life. All eukaryotic and prokaryotic organisms depend onelectron transferring and transporting elements which include metalcontaining hemes and nonmetal containing molecules such as flavins toconvert the energy stored in the chemical bonds of foodstuffs into aform utilizable for the maintenance of the highly negative entropicstate of life. The chemical energy conversion process generally involvesa coupled series of electron carriers which is called an electrontransport chain.

Free radicals of oxygen are produced during aerobic respiration inmitochondria as electrons are carried by electron carriers of theelectron transport chain to the ultimate electron acceptor, oxygen, andsuperoxide and peroxide, partial reduction products of oxygen, arecontinuously produced during cytosolic hydroxylation and oxygenationreactions as well as during other reactions which involve enzymaticreduction of oxygen. The cytosol as well as mitochondria of aerobiccells contain high concentrations of the enzyme superoxide dismutasewhich converts superoxide into hydrogen peroxide and molecular oxygen.Oxygen radicals which include hydrogen peroxide and superoxide are foundin greater concentration in the mitochondria relative to the cytosolbecause reduction of oxygen occurs to a greater extent in the formercompartment; however, appreciable concentration are found in bothcompartments.

Luminides are agents which are permeant to the desired biologicalcompartment which undergo an oxidation reduction reaction with thetarget cell's electron carriers or react with free radicals produced asa consequence of electron transport and release a drug moiety into thedesired compartment in active form to effect a greater therapeuticeffect or therapeutic ratio relative to the free C agent as aconsequence of altered pharmacokinetics or pharmacodynamics such as adesirable kinetics of release, a resistance to inactivation orexcretion, greater solubility, enhanced absorption, a diminishedtoxicity, or greater access to the cellular or biological compartmentwhich is the site of action of C.

Luminide agents are three or four part molecules where each part is afunctionality with a defined purpose. Exemplary Luminides are A-B-C,D-A-B-C, A-D-B-C and ##STR2## where A represents a functionality whichundergoes an oxidation reduction reaction where electrons aretransferred directly between A and the target cell's electron carriersor the electrons are transferred indirectly through an electron transferfunctionality, D, which is described in more detail below.Alternatively, A represents a functionality which undergoes a reactionwith free radicals of oxygen which are produced as a consequence ofelectron transport. An excited state is produced in A as a consequenceof its participation in one of these reactions. Then A undergoesintramolecular energy transfer from its own excited state to the Bfunctionality which is an energy acceptor. Upon receiving energy from A,B achieves an excited state which relaxes through heterolytic cleavageof the covalent bond of B with C where C is a drug moiety which isreleased into the environment. D serves as an electron transferfunctionality which gains (loses) electrons from (to) the environmentand donates (accepts) electrons to (from) A to activate it so that theenergy of excited A is transferred to B with release of C as occurs forthe three functionality case. In both cases, free C is a drug molecule.The released drug molecule effects a therapeutic functional change by amechanism which comprises receptor mediated mechanisms includingreversible and irrereversible competitive agonism or antagonismincluding a molecle known as a suicide substrate or a transition stateanalogue mechanism or a noncompetitive or uncompetitive agonism orantagonism or the action is by a nonreceptor mediated mechanismincluding a "counterfeit incorporation-mechanism".

The energy donating funtionality, A, is a molecule which reacts aspreviously described to form an excited state of high enough energy sothat this subsequently transferred energy is of sufficient magnitude tobreak the covalent bond between the drug functionality, C, and theenergy acceptor functionality, B. Chemiluminescent molecules can formhighly excited states of the proper magnitude of energy, can undergooxidation reduction reactions or react with free radicals, and possess ametastable excited state from which intramolecular energy transfer canoccur; thus, they can serve as the A functionality. In general,chemiluminescent molecules relevant to this invention can be placed intothree categories: 1) molecules undergoing reaction involving peroxidesand oxygen free radicals; 2) molecules undergoing reaction involvingoxidation or reduction and 3) molecules undergoing both reaction withperoxides and oxygen free radicals followed by an oxidation or reductionreaction. Molecules of the first category include Lophine and itsderivatives, acridinium esters and acridans, tetraphenylpyrrole,phthalhydrazides, acyloins, biacridinium salts, vinylcarbonyls,vinylnitriles, tetrakis (dimethylamino) ethylene, acylperoxides,indoles, tetracarbazoles and active oxalates.

Molecules belonging to the second category include ruthenium chelates 2,6-diaminopyrene, or cation radicals and molecules which follow aChemically Initiated Electron Exchange Luminescence mechanism such ascertain dioxetans and dioxetanones. Dioxene derivatives belong to thethird category. They form a dioxetan by reation with superoxide and thenproduce efficient chemiluminescence by a CIEEL mechanism.

As an example from the first category, the chemiluminescent compound,luminol, has a chemiluminescent maximum in the region 390-400 nm in anaqueous solution. Chemiluminescence is produced by the reaction ofluminol with oxygen free radicals where a large fraction of the productmolecules are formed in their excited state. The nature of the excitedstate is electronic, and it has a mean lifetime of the order of 10⁻⁸seconds which is typically ten thousand times the period of a molecularvibration. Emission involves a quantum mechanically allowed singlet tosinglet transition with energy of the order of 75 Kcal/mole. The quantumyield for forming the excited electronic state is 0.5. Because luminolundergoes a chemiluminescent reaction with oxygen radicals, thiscompound has been used as a molecular probe for these radicals bylinkage to a molecule which directs the probe to a cellular compartment.For example, when luminol is attached to carnitine, the probe istransported into mitochondria and the intensity of chemiluminescenceproduced is proportional to the magnitude of electron transport activitywhich produces oxygen radicals. The chemiluminescent molecule,lucigenin, is also used as a probe for oxygen free radicals.

As for members of the second category, chemiluminescent molecules whichundergo a redox reaction to produce an excited state react directly withelectron carriers of the cell or undergo a redox reaction with theelectron transfer functionality D.

As for the third category, a D functionality is optional. Achemiluminescent molecule of this category reacts with oxygen freeradicals and forms an excited state, and chemiluminescence is producedbut properties such as quantum yield or the relative ratio of singlet totriplet excited state can be altered by the transfer of electronsinvolving for example a D functionality. See Table 1 below forchemiluminescent molecules.

                  TABLE 1                                                         ______________________________________                                        Representative Chemiluminescent Molecules                                     Name          Structure                                                       ______________________________________                                        2,6-diaminopyrene                                                                            ##STR3##                                                       Aminophthalhydrazide                                                                         ##STR4##                                                       Dioxene                                                                                      ##STR5##                                                       Imidazole derivatives                                                                        ##STR6##                                                       Sulfonyloxamides                                                                             ##STR7##                                                       Indole derivatives                                                                           ##STR8##                                                       Tetrakis(dialkylamino)- ethylene                                                             ##STR9##                                                       2,5,7,8-tetraoxabicyclo-  4.2.0.! octane                                                     ##STR10##                                                      Dioxetan                                                                                     ##STR11##                                                      Lucigenin                                                                                    ##STR12##                                                      Lophine                                                                                      ##STR13##                                                      Acridinium esters                                                                            ##STR14##                                                      Active oxalate                                                                               ##STR15##                                                      Tris-2,2'-bipyridinedi- chlororuthenium (II)                                                 ##STR16##                                                      Dioxetanone                                                                                  ##STR17##                                                      Dipheyl peroxide                                                                             ##STR18##                                                      ______________________________________                                    

Exemplary energy acceptor molecules include those which demonstratephotochromic behavior with electromagnetic radiation and bleachingagents. If the A functionality is chemiluminescent, then the Bfunctionality is such that the photodissociative drug release spectrumof B overlaps the chemiluminescence spectrum of A.

Triarylmethane dyes react with cyanide to form nitriles calledleucocyanides which liberate cyanide ion with a quantum yield ofapproximately one when irradiated with UV light in the wavelength rangeof 250 to 320 nm. ##STR19## The spectrum of the photorelease reaction ofcyanide ion can be extended to longer wavelengths in the case oftriarylmethane dyes by substitutions of a naphthylene for an aryl groupand also by using cationic polymethine dyes. The latter form nitriles,which are thermally stable, by the reaction of the carbonium ion of thedye with cyanide. The formation of the nitrile causes the colored dye tobe bleached as is the case with triarylmethane dyes, and cyanide isreleased as the dye becomes colored upon absorption of 320-415 nm.Reversible bleaching by an agent and coloration by light is photochromicbehavior.

Cationic dyes demonstrate this behavior and include di andtriarylmethane dyes, triarylmethane lactones and cyclic ether dyes,cationic indoles, pyronines, phthaleins, oxazines, thiazines, acridines,phenazines, and anthocyanidins, and cationic polymethine dyes and azoand diazopolymethines, styryls, cyanines, hemicyanines,dialkylaminopolyenes, and other related dyes. See Table 2 below forstructures for salt isomerism-type photochromic dyes. These photochromicmolecules form covalent bonds with a number of agents called bleachingagents because they convert the compounds from colored to colorless formduring bond formation. Bleaching agents are diverse and includehydroxide, cyanide, azide, bisulfide, and sulfite compounds,thiocyanate, ferrocyanide, chromate, tetraborate, acetate, nitrite,carbonate, citrate, aluminate, tungstate, molybdate, methoxide,2-methoxyethoxide, cinnamate, and p-methoxycinnamate salts, and thiolsand amines.

                                      TABLE II                                    __________________________________________________________________________    Dye Name or Structure; CI Name and                                            Number; Other Names                                                           __________________________________________________________________________    Malachite Green               42000                                           Helvetia Green                42020                                           Basic Blue 1                  42025                                           Brilliant Blue                                                                Setoglaucine                                                                  Basic Green 1                 42040                                           Brilliant Green                                                               Acid Blue 1                   42045                                           Xylene Blue VS                                                                Patent Blue V                                                                 Alphazurine 2G                                                                Acid Blue 3                   42051                                           Brilliant Blue V                                                              Patent Blue V                                                                 Food Green 3                  42053                                           FDC Green 3                                                                   Acid Green 6                  42075                                           Light Green SF Bluish                                                         Acid Blue 7                   42080                                           Xylene Blue AS                                                                Patent Blue A                                                                 Acid Green 3                  42085                                           Acid Blue 9                   42090                                           Erioglaucine                                                                  Acid Green 5                  42095                                           Light Green SF Yellowish                                                      Acid Green 9                  42100                                           Erioviridene B                                                                Acid Blue 147                 42135                                           Xylene Cyanol FF                                                              Basic Red 9                   42500                                           Pararosaniline                                                                Basic Violet 14               42510                                           Fuchsin                                                                       Magenta                                                                       Basic Fuchsin                 42510B                                          Basic Violet 2                42520                                           New Fuchsin                                                                   New Magenta                                                                   Hoffman Violet                42530                                           Iodine Violet                                                                 Basic Violet 1                42535                                           Methyl Violet                                                                 Basic Violet 13               42536                                           Methyl Violet 6B                                                              Basic Violet 3                42555                                           Crystal Violet                                                                Gentian Violet                                                                Iodine Green                  42556                                           Basic Blue 8                  42563                                           Victoria Blue 4R                                                              Acid Blue 13                  42571                                           Fast Acid Violet 10B                                                          Acid Blue 75                  42576                                           Eriocyanine A                                                                 Methyl Green                  42585                                           Ethyl Green                   42590                                           Basic Violet 4                42600                                           Ethyl Violet                                                                  Acid Violet 49                42640                                           Wool Violet 5BN                                                               Acid Blue 15                  42645                                           Brilliant Milling Blue B                                                      Acid Violet 17                42650                                           Acid Violet 6B                                                                Wool Violet 4BN                                                               Formyl Violet                                                                 Acid Violet 5BS Conc.                                                         Acid Violet 19                42685                                           Acid Fuchsin                                                                  Red Violet 5R                 42690                                           Acid Blue 22                  42755                                           Aniline Blue                                                                  Soluble Blue                                                                  Solvent Blue 3                42775                                           Acid Blue 93                  42780                                           Methyl Blue                                                                   Aurin                         43800                                           Mordant Blue 3                43820                                           Eriochrome Cyanine R                                                          Acid Green 16                 44025                                           Naphthalene Green V                                                           Pontacyl Green NV Extra                                                       Basic Blue 11                 44040                                           Victoria Blue R                                                               Basic Blue 15                 44085                                           Night Blue                                                                    Acid Green 50                 44090                                           Wool Green S                                                                  Kiton Green S Conc.                                                           Basic Green 3                                                                 Sevron Green B                                                                Brilliant Blue F & R Extra                                                    Brilliant Green Sulfonate                                                     Hexakis(hydroxyethyl)                                                         Pararosaniline                                                                 ##STR20##                                                                    New Green                                                                      ##STR21##                                                                    Phenolphthalein                                                                ##STR22##                                                                    Malachite Green Ethiodide                                                      ##STR23##                                                                    Hydroxyalkylated Pararosanilines                                               ##STR24##                                                                    Hydroxyalkylated New Fuchsins                                                  ##STR25##                                                                    New Yellow                                                                     ##STR26##                                                                    Doebner's Violet                                                               ##STR27##                                                                    New Red                                                                        ##STR28##                                                                    Bis(hydroxyethyl) Doebner's Violet                                             ##STR29##                                                                    "New Magenta"                                                                  ##STR30##                                                                    Tetrakis(hydroxyethyl) Doebner's Violet                                        ##STR31##                                                                    Trichloro Crystal Violet                                                       ##STR32##                                                                    Slow Red                                                                       ##STR33##                                                                     ##STR34##                                                                     ##STR35##                                                                     ##STR36##                                                                     ##STR37##                                                                     ##STR38##                                                                     ##STR39##                                                                     ##STR40##                                                                     ##STR41##                                                                     ##STR42##                                                                     ##STR43##                                                                     ##STR44##                                                                     ##STR45##                                                                     ##STR46##                                                                    __________________________________________________________________________    .sup.a Only the cyanide, bisulfite, and hydroxide ions are considered,        regardless of the other anions present in the solution.                       .sup.b More detailed descriptions of the compositions of photochromic         materials tested are given in Macnair's review  255;                          tables 1A-4!.                                                                 .sup.c Ethanol.                                                               .sup.d Diethyl ether.                                                         .sup.e 1,2-Dichloroethane.                                                    .sup.f 1,1-Dichloroethane, cyclohexane-1,1-dichloroethane, or                 cyclohexane-1,2-dichloroethane mixtures.                                      .sup.g Benzene.                                                               .sup.h Dimethylsulfoxide, neat and aqueous.                                   .sup.i Acetone.                                                               .sup.j Acetic acid.                                                           .sup.k Ethyl acetate.                                                         .sup.l Ethyl bromide.                                                         .sup.m 2-Methoxyethanol.                                                      .sup.n Chloroform.                                                            .sup.o Ethanol with KCN.                                                      .sup.p Ethanol wiih KOH.                                                      .sup.q Carboxylic acids-acetic to stearic; hydrocinnamic acid; ethyl and      butyl acid phthalates.                                                        .sup.r Octadecylnitrile, tributyl phosphate, aniline, 2-(p-tert-butylpheno    xy)ethanol, tetraethyleneglycol dimethyl ether,                               or poly(ethylene glycols).                                                    .sup.s Amides-formamide to stearamide; methylformamide or                     methylacetamide; dimethyl- or diethyl-formamide or acetamide.                 .sup.t Three-to-one solutions of cellulose acetate with any of the            following five-to-one plasticizer mixtures:                                   butyl stearate, Polyethylene Glycol 600-butyl acetoxystearate,                butyl stearate, or Dowanol EP-butyl acetoxystearate.                          .sup.u Water containing SO.sub.2.                                             .sup.v Water containing bisulfite and papain.                                 .sup.w Poly(vinyl alcohol) with dimethylsulfoxide (5:1).                      .sup.x Films, containing residual solvent, cast from the following            solutions: ethanol-acetone solutions of vinyl                                 acetate-vinyl alcohol copolymer; aqueous poly(vinyl alcohol); aqueous         poly(vinyl pyrrolidone); or aqueous methyl                                    vinylether-maleic acid copolymer.                                             .sup.y Methanol-dioxane with aqueous NH.sub.4 HSO.sub.3.                      .sup.z Paper impregnated with a toluene solution of poly(methyl               methacrylate), stearic acid, and                                              2-(p-tert-butylphenoxy)ethanol, then dried.                                   .sup.aa Intramicellar impregnation of cellulose with the following            swelling agents: n-propylamine, n-butylamine,                                 n-hexylamine, 2-aminoethanol, dimethylformamide, acetic acid,                 dimethylsulfoxide, methylacetamide, dimethylacetamide,                        or formamide.                                                                 .sup.bb Films cast from an approximately 4:3 mixture of a 20% solution        and cellulose acetate butyrate in toluene-ethyl                               acetate (1:1) and triallycyanurate in dioxane.                                .sup.cc Films cast from a 2:1 mixture of a 25% solution of cellulose          acetate butyrate in toluene-ethyl acetate (1:1) and                           the titanium esters of N,N,N', N'-tetrakis(2-hydroxypropyl)                   ethylenediamine.                                                              .sup.dd Pure water.                                                           .sup.ee Films cast from aqueous gelatin or other hydrocolloids.               .sup.ff Dimethylsulfoxide with methanolic KCN.                                .sup.gg 2-Methoxyethanol with methanolic KCN.                                 .sup.hh Water or aqueous methanol containing bisulfite.                       .sup.ii Paper impregnated with m-dimethoxybenzene, acetonitrile, acetic       acid, or phenyl methyl carbinol.                                              .sup.jj Ethanol-benzene.                                                      .sup.kk Aqueous ethanol, methanol, aqueous methanol, aqueous acetone,         benzene-methanol, carbon tetrachloride-methanol,                              cyclohexane-methanol, or chloroform-methanol.                                 .sup.ll Films cast from 3:1 solutions of cellulose acetate and either         Polyethylene Glycol 600 ® or ethylene                                     glycol phenyl ether as plasticizer.                                           .sup.mm Films, containing residual solvent, cast from solutions of either     cellulose acetate in 2-methoxyethanol or                                      poly(vinyl alcohol) in aqueous ethanol.                                       .sup.nn Films, containing residual solvent, cast from solutions of either     cellulose acetate butyrate in 2-methoxyethanol                                or poly(vinyl acetate) in methanol.                                           .sup.oo Ethanol containing ammonia.                                           .sup.pp Aqueous methanol containing NH.sub.4 HSO.sub.3  and urease.           .sup.qq Aqueous methanol containing NH.sub.4 HSO.sub.3, with or without       sodium dithionite.                                                            .sup.rr Aqueous acid at pH 1.                                                 .sup.ss Aqueous ammonia containing KCN.                                       .sup.tt Paper impregnated with aqueous solutions with or without              hydrocolloids.                                                                .sup.uu 2-Methoxyethanol containing HCl.                                      .sup.vv Aqueous methanol containing NH.sub.4 HSO.sub.3, and glucose           oxidase.                                                                      .sup.ww 9:1 Methanol-water.                                                   .sup.xx Aqueous NaOH.                                                          ##STR47##                                                                     ##STR48##                                                                     ##STR49##                                                                     ##STR50##                                                                     ##STR51##                                                                     ##STR52##                                                                    __________________________________________________________________________    Photochromic Polymethine Dyes                                                 __________________________________________________________________________    α, ω-bis(p-Dimethylaminophenyl)polyenes                            ##STR53##                                                                    Ar                           n                                                __________________________________________________________________________    C.sub.6 H.sub.5              0, 1, 2                                          4-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                                        0, 1, 2                                          4-(CH.sub.3).sub.2 CHC.sub.6 H.sub.4                                                                       0, 1, 2, 3, 4                                    4-CH.sub.3 OC.sub.6 H.sub.4  0, 1, 2                                          4-C.sub.4 H.sub.9 OC.sub.6 H.sub.4                                                                         0, 1, 2                                          3-CH.sub.3 C.sub.6 H.sub.4   1, 2                                             4-t-C.sub.4 H.sub.9 C.sub.6 H.sub.4                                                                        1, 2                                             4-C.sub.2 H.sub.5 OC.sub.6 H.sub.4                                                                         1, 2                                             4-C.sub.5 H.sub.11 C.sub.6 H.sub.4                                                                         1, 2                                             4-FC.sub.6 H.sub.4           1                                                4-F.sub.3 CC.sub.6 H.sub.4   1                                                2-(C.sub.6 H.sub.5).sub.2 NC.sub.6 H.sub.4                                                                 1                                                3,4-H.sub.2 N(OCH.sub.3)C.sub.6 H.sub.3                                                                    1                                                2-Naphthyl                   1, 2                                             4-ClC.sub.6 H.sub.4          2                                                2,4-Cl.sub.2 C.sub.6 H.sub.3 2                                                1-Naphthyl                   2                                                __________________________________________________________________________    α, α-bis(p-dimethylaminophenyl)polyenes                            ##STR54##                                                                    R                            R                                                __________________________________________________________________________     ##STR55##                                                                                                  ##STR56##                                        ##STR57##                                                                     ##STR58##                                                                                                  ##STR59##                                        ##STR60##                                                                                                  ##STR61##                                        ##STR62##                   CHNN(C.sub.6 H.sub.5).sub.2                       ##STR63##                                                                                                  ##STR64##                                                                     ##STR65##                                        ##STR66##                                                                                                  ##STR67##                                        ##STR68##                                                                                                  ##STR69##                                       __________________________________________________________________________    Miscellaneous polyenes                                                        __________________________________________________________________________     ##STR70##                                                                     ##STR71##                                                                     ##STR72##                                                                     ##STR73##                                                                     ##STR74##                                                                     ##STR75##                                                                     ##STR76##                                                                    Basic Red 13                                                                           ##STR77##                                                            Basic Violet 7                                                                Basic Red 14 Basic Red 15 Basic Violet 15                                              ##STR78##                                                             ##STR79##                                                                     ##STR80##                                                                     ##STR81##                                                                     ##STR82##                                                                     ##STR83##                                                                     ##STR84##                                                                     ##STR85##                                                                     ##STR86##                                                                     ##STR87##                                                                     ##STR88##                                                                     ##STR89##                                                                     ##STR90##                                                                     ##STR91##                                                                     ##STR92##                                                                     ##STR93##                                                                     ##STR94##                                                                     ##STR95##                                                                     ##STR96##                                                                     ##STR97##                                                                     ##STR98##                                                                     ##STR99##                                                                     ##STR100##                                                                    ##STR101##                                                                    ##STR102##                                                                    ##STR103##                                                                    ##STR104##                                                                    ##STR105##                                                                    ##STR106##                                                                   __________________________________________________________________________    SALT-ISOMERISM TYPE PHOTOTROPIC DYES                                          __________________________________________________________________________    Night Blue                                                                     ##STR107##                                                                   Victoria Blue R                                                                ##STR108##                                                                   Brilliant Milling Blue B                                                      Brilliant Blue F & R Ex.                                                      Eriocyanine A                                                                  ##STR109##                                                                   Methyl Blue                                                                    ##STR110##                                                                   Aniline Blue                                                                   ##STR111##                                                                   Eriochrome Cyanine R                                                           ##STR112##                                                                   Methyl Violet 6B                                                               ##STR113##                                                                   Iodine Green                                                                   ##STR114##                                                                   Aniline Blue                                                                   ##STR115##                                                                   Wool Violet 5 BN                                                               ##STR116##                                                                   Wool Violet 4 EM                                                               ##STR117##                                                                   Light Green SF                                                                Yellowish                                                                      ##STR118##                                                                   Iodine Violet                                                                  ##STR119##                                                                   Methyl Violet                                                                  ##STR120##                                                                   Crystal Violet                                                                 ##STR121##                                                                   Ethyl Violet                                                                   ##STR122##                                                                   Acid Green L Extra                                                             ##STR123##                                                                   Erioviridene B                                                                 ##STR124##                                                                   Light Green SF                                                                 ##STR125##                                                                   Victoria Green                                                                (Malachite Green)                                                              ##STR126##                                                                   Red-Violet 5R                                                                  ##STR127##                                                                   Brilliant Green "B"                                                            ##STR128##                                                                   Di- 4(N,N-diethylamine)phenyl!- 4-(N,N-diethyl-                               amine-2-methyl) phenyl! methyl carbonium                                       ##STR129##                                                                   Tri- 4(N,N-dipropylamino)phenyl! methyl carbonium                              ##STR130##                                                                   Di- 4(N,N-diethylamino)phenyl!- 4(ethylamino)-                                phenyl! methyl carbonium                                                       ##STR131##                                                                   Di- 4(N,N-diethylamino)phenyl!- 4(N,N-diethyl-                                amino)naphthyl! methyl carbonium                                               ##STR132##                                                                   Di- 4(N,N-dimethylamino)phenyl!- 4(hydroxy)phenyl!                            methyl carbonium                                                               ##STR133##                                                                   Tri- 4(N-propylamino)phenyl! methyl carbonium                                  ##STR134##                                                                   Hectolene Blue DS-1398                                                        Hectolene Blue DS-1823                                                        Sevron Brilliant Red 4G                                                       Di- 4(N,N-dimethylamino)phenyl!- 4(hydroxy)phenyl!                            methyl carbonium                                                               ##STR135##                                                                   Tri- 4(N-propylamino)phenyl! methyl carbonium                                  ##STR136##                                                                   Hectolene Blue DS-1398                                                        Hectolene Blue DS-1823                                                        Sevron Brilliant Red 4G                                                       Genacryl Red 6B                                                               Genacryl Pink G                                                               Sevron Brilliant - Red B                                                      Sevron Brilliant - Red 3B                                                     1,5-bis- 4(N,N-dimethylamino)phenyl!-1,5-bis-                                 (phenyl)divinyl carbonium trifluoroacetate                                     ##STR137##                                                                   1,1,3,3-tetrakis 4(N,N-dimethylamino)phenyl!                                  vinyl carbonium perchlorate                                                    ##STR138##                                                                   1,5-bis- 4(N,N-dimethylamino)phenyl!-1,5-bis-                                 (phenyl) divinyl carbonium p-toluenesulfonate                                  ##STR139##                                                                   1,7-bis 4(N,N-dimethylamino)phenyl!-1,7-bis-                                  (2,4-dichlorophenyl) trivinyl carbonium perchlorate                            ##STR140##                                                                   Di- 4(N,N-dimethylamino)phenyl vinyl!- 2,4-di-                                phenyl-6-methane thiopyran! methyl carbonium perchlorate                       ##STR141##                                                                   1,7-bis- 4(N,N-dimethylamino)phenyl!-1,7-bis-                                 (4-chlorophenyl) trivinyl carbonium trifluoroacetate                           ##STR142##                                                                   1,1,3-tris- 4-(N,N-dimethylamino)phenyl! divinyl                              carbonium perchlorate                                                          ##STR143##                                                                   1,1,7,7-tetrakis- 4-(N,N-dimethylamino)phenyl!                                trivinyl carbonium perchlorate                                                 ##STR144##                                                                   1,3-bis- 4-(N,N-dimethylamino)phenyl!-1,3-bis-                                (phenyl) vinyl carbonium perchlorate                                           ##STR145##                                                                   1,1,5,5-tetrakis- 4-(N,N-dimethylamino)phenyl!                                divinyl carbonium perchlorate                                                  ##STR146##                                                                   1,5-bis- 4-(N,N-dimethylamino)phenyl!-1,5-bis-                                (phenyl) divinyl carbonium perchlorate                                         ##STR147##                                                                   1,7-bis- 4-(N,N-dimethylamino)phenyl!-1,7-bis-                                (phenyl) trivinyl carbonium trifluoroacetate                                   ##STR148##                                                                   1(1,3,3-trimethyl indoline)-2- 4-(N,N-dimethyl-                               amino)phenyl! ethylene carbonium perchlorate                                   ##STR149##                                                                   1(1,3,3-trimethyl indoline)-4- 4-(N,N-dimethyl-                               amino)phenyl! butylene carbonium perchlorate                                   ##STR150##                                                                   1,1,3,3-tetrakis- 4(N,N-diethylamino)phenyl!                                  vinyl carbonium perchlorate                                                    ##STR151##                                                                   1,1-bis- 4-(N,N-diethylamino)phenyl!-3,3-bis-                                  4-(N,N-dimethylamino)phenyl! vinyl carbonium perchlorate                      ##STR152##                                                                   1,1,5,5-tetrakis- 4-(N,N-diethylamino)phenyl!                                 divinyl carbonium perchlorate                                                  ##STR153##                                                                   1,1-bis- 4-(N,N-dimethylamino)phenyl!-3- 4-(amino)                            phenyl!-3-methylvinyl carbonium perchlorate                                    ##STR154##                                                                   Tris- 1,1-bis- 4(N,N-dimethylamino)phenyl!                                    ethylene! methyl carbonium perchlorate                                         ##STR155##                                                                   Tris- 1,1-bis- 4-(N,N-diethylamino)phenyl!                                    ethylene! methyl carbonium perchlorate                                         ##STR156##                                                                   1,1,5-tris- 4-(N,N-dimethylamino)phenyl! divinyl                              carbonium perchlorate                                                          ##STR157##                                                                   N 4-(N,N-dimethylamino) cinnamylidene! auramine                                ##STR158##                                                                   1,1-bis- 4-(N,N-dimethylamino)phenyl-3,4-bis-                                 (phenyl)!-3,4-diazo butene carbonium                                           ##STR159##                                                                   1,1,5,5-tetrakis- 4-(N,N-dimethylamino)phenyl!-                               2,3-diazo pentene carbonium                                                    ##STR160##                                                                   N-(N',N'-dimethylamino cinnamylidene)-N,N-diphenyl                            ammonium                                                                       ##STR161##                                                                   Azo Polymethines                                                              Dyes of the general structural type                                            ##STR162##                                                                    ##STR163##                                                                    ##STR164##                                                                   Photochromic diazopolymethines                                                 ##STR165##                                                                   1,1,5,5-tetrakis- 4-(N,Np-dimethylamino)phenyl!-                              2,3-diazo pentene carbonium                                                    ##STR166##                                                                   1,1-bis- 4-(N,N-dimethylamino)phenyl-3,4-bis-                                 (phenyl)!-3,4-diazo butene carbonium                                          __________________________________________________________________________

The drug functionality, C, includes any molecule which exhibitsbleaching behavior with the B functionality and has an increasedtherapeutic effect or therapeutic ratio as a consequence of its deliveryas part of a Luminide agent. For example, Foscarnet, a viral reversetranscriptase inhibitor possesses both a carboxylate and phosphate groupwhich will bleach photochromic compounds; 4-bromocrotonyl-CoA, anacetoacetyl-CoA thiolase inhibitor, possesses a thiol group which willbleach photochromic compounds; L-3-iodo-a-methyltyrosine, a tyrosinehydroxylase inhibitor, possesses a carboxylate group which will bleachphotochromic compounds, and captopril, an antihypertensivepharmaceutical, possesses both a sulfide and carboxylate group whichwill bleach photochromic compounds. Furthermore, the pharmacokineticsand/or pharmacodynamics of these agents are altered via delivery to thesite of action by way of a luminide agent such that the therapeuticeffect or therapeutic ratio is enhanced.

Other drugs which are not inherently photochromic bleaches in that theylack a nucleophilic group which will form a reversible covalent bondwith the B functionality can be derivatized with a known bleachingnucleophilic group such as cinnamate, sulfite, phosphate, carboxylate,thiol, or amine group to transform them into bleaching agents of the Bfunctionality such as a cationic dye. See Table 3 below for thestructure of a exemplary drug molecules.

                                      TABLE 3                                     __________________________________________________________________________    Representative Drug Molecules.                                                Name        Structure                                                         __________________________________________________________________________    Captopril                                                                                  ##STR167##                                                       Prostaglandin E.sub.2                                                                      ##STR168##                                                       2,3-dichloro-α-methyl- benzylamine                                                   ##STR169##                                                       3'-deoxy-S-adenosyl-L- homocysteine                                                        ##STR170##                                                       Sinefungin                                                                                 ##STR171##                                                       3,5-diiodo-4-hydroxy- benzoic acid                                                         ##STR172##                                                       6,6'-dithiobis (9- B-D-ribofuranosylpurine)                                                ##STR173##                                                       γ-aminobutyric acid                                                                 H.sub.2 NCH.sub.2 CH.sub.2 CH.sub.2 COOH                          Gabaculine                                                                                 ##STR174##                                                       N-(5'-phosphopyridoxy)- 4-aminobutyric acid                                                ##STR175##                                                       4-amino-hex-5-enoic acid                                                                   ##STR176##                                                       Baclofen                                                                                   ##STR177##                                                       Adenosine                                                                                  ##STR178##                                                       3-hydroxy-3-methyl- glutarate                                                              ##STR179##                                                       Campactin                                                                                  ##STR180##                                                       But-3-ynoyl-CoA                                                                            ##STR181##                                                       Suramin                                                                                    ##STR182##                                                       L-3-iodotyrosine                                                                           ##STR183##                                                       L-3-iodo-α-methyltyrosine                                                            ##STR184##                                                       Disodium cromoglycate                                                                      ##STR185##                                                       Adenosine 3',5'-cyclic monophosphate                                                       ##STR186##                                                       D,L-B-(5-hydroxy-3- indolyl)-α-hydra- zinopropionic                                  ##STR187##                                                       D,L-α-hydrazino-α- methyldopa                                                  ##STR188##                                                       α-methyldopa                                                                         ##STR189##                                                       5-(3,4-dihydroxycinna- moyl)salicylic acid                                                 ##STR190##                                                       N-(phosphonacetyl)- L-aspartate                                                            ##STR191##                                                       P-glycolohydroxamate                                                                       ##STR192##                                                       5-(p-sulfamylphenyl- azosalicylic acid                                                     ##STR193##                                                       Coformycin                                                                                 ##STR194##                                                       Formycin B                                                                                 ##STR195##                                                       Thioinosinate                                                                              ##STR196##                                                       Phosphonoformate                                                                           ##STR197##                                                       Phosphonoacetate                                                                           ##STR198##                                                       Ridavirin                                                                                  ##STR199##                                                       Sotalol                                                                                    ##STR200##                                                       Cimetidine                                                                                 ##STR201##                                                       Fuscaric acid                                                                              ##STR202##                                                       2-mercaptoethylamine                                                                      HSCH.sub.2 CH.sub.2 NH.sub.3.sup.+                                Mimosine                                                                                   ##STR203##                                                       U-7130                                                                                     ##STR204##                                                       Iproniazid                                                                                 ##STR205##                                                       Trans-4-aminoocrotonic                                                                    H.sub.2 NCH.sub.2 CHCHCOOH                                        acid                                                                          NSD 1055                                                                                   ##STR206##                                                       Nicotinic acid                                                                             ##STR207##                                                       Kynurenic acid                                                                             ##STR208##                                                       Lentysine                                                                                  ##STR209##                                                       Orotic acid                                                                                ##STR210##                                                       Polyoxin D                                                                                 ##STR211##                                                       Cephalosporin                                                                              ##STR212##                                                       Penicillin                                                                                 ##STR213##                                                       __________________________________________________________________________

The electron transfer functionality, D, includes molecules which undergoa redox reaction which transfers electrons between the electron carriersand the A functionality where a redox reaction of A results in itsactivation to an excited energy state. The D functionality can be anatural electron carrier such as ubiquinone or a synthetic electroncarrier such as methylene blue, phenazine methosulfate, or2,6-dichlorophenolindophenol. Structures of electron transfer moleculesappear below in Table 4.

                  TABLE 4                                                         ______________________________________                                        Representative Electron Transfer Molecules.                                    ##STR214##                                                                    ##STR215##                                                                    ##STR216##                                                                    ##STR217##                                                                    ##STR218##                                                                   ______________________________________                                    

A Representative Luminide

A representative luminide is the product of the covalent linkage of thepolymethine dye with a bleaching drug such as Foscarnet and with achemiluminescent reactive molecule such as luminol. This conjugaterepresents a molecule which releases Foscarnet in the presence of oxygenfree radicals. The energy of the reaction of luminol with oxygenradicals undergoes intramolecular electronic energy transfer byradiative and nonradiative mechanisms. The latter dominate and includecoulombic interactions, dipole-dipole resonance, and exchangeinteraction. These processes increase the quantum yield for drug releaseabove that which would be produced by luminescence transfer alone. Forexample, Forster, in a quantum mechanical treatment of resonancetransfer, in the region of spectral overlap involving allowedtransitions of two well separated molecules has only considereddipole-dipole interactions in deriving an experimentally verifiedformula which predicts a distance of 5-10 nm as the distance at whichtransfer and spontaneous decay of the excited donor are equallyprobable. The formula predicts the transfer probability is inverselyproportional to the separation distance raised to the sixth power.However, the donor and accepter functionalities of a Luminide arecovalently linked;

thus, since the separation distance is of the order of angstroms, thetransfer probability is great. In fact, the efficiency of transfer hasbeen studied in certain molecules which consist of two independentchromophores separated by one or more saturated bonds. In such cases,energy transfer over large distances has been observed to be inagreement with predictions from Forster's Theory.

The Luminides can be prepared by known reactions where necessary,appropriate derivatives of the subunits are formed before coupling.

Representative examples of appropriate derivatization and couplingreactions are given in the following examples, illustrating thepreparation of representative Luminides. These examples are not to betaken as an exhaustive listing, but only illustrative of thepossibilities according to the present invention.

Representative Luminides with Outline of Synthetic Pathway.

Luminides synthesis involves the chemical joining of three or fourfunctionalities. A representative luminide of three functionalitiescomprises an energy donor molecule such as a chemiluminescent molecule,an energy acceptor molecule such as a photochromic molecule, and a drug.A representative luminide of four functionalities comprises thementioned three functionalities and also an electron transferfunctionality which can undergo an oxidation reduction reaction.

A three group Luminde can be formed by condensing a photochromic dyefunctionalized as an acid chloride with a chemiluminescent moleculepossessing an alcoholic or amino group to form an ester or amide. Theluminide pharmaceutical is then formed by addition of the drug bleachingagent. An exemplary pathway of this type appears in example 1.

Alternately, the chemiluminescent and/or electron transfer functionalitycan be linked to the energy acceptor functionality by formation of anester or amide where the former functionality/functionalities is/are anacid halide as demonstrated in example 15.

Also, functionalities of the electron transfer and energy donor type canbe linked to the energy acceptor part by an acylation reaction asdemonstrated in examples 2, 3 and 8; by nucleophillic substitution asdemonstrated in examples 4, 5, 6, 7, 9, 10, 12 and 17; by a carbanionmechanism as demonstrated in example 11; by a Grignard reaction asdemonstrated in example 14, by a tosylate mechanism as demonstrated inexample 13, or by a Wittig reaction as demonstrated in example 16.Similar reaction pathways can be used to link chemiluminescent moleculesto energy donor molecules. The list of examples of reaction pathways isintended to be examplary and other pathways can be devised by oneskilled in the art. Furthermore, only a representative number ofluminides are shown and a vast number of other novel luminides can bemade by one skilled in the art following the guidelines hereindisclosed.

And, the disclosed exemplary luminides, and components: chemiluminescentmolecules, photochromic molecules, energy transfer molecules, and drugmolecules can be modified to further candidate components by addition offunctional groups by one skilled in the art. Representative groupsinclude aklyl, cycloalkl, alkoxycarbonyl, cyano, carbamoyl, heterocyclicrings containing C, O, N, S, sulfo, sulfamoyl, alkoxysulfonyl,phosphono, hydroxyl, halogen, alkoxy, alkylthiol, acyloxy, aryl,alkenyl, aliphatic, acyl, carboxyl, amino, cyanoalkoxy, diazonium,carboxyalkylcarboxamido, alkenyl, thio, cyanoalkoxycarbonyl,carbamoylalkoxycarbonyl, alkoxy carbonylamino, cyanoalkylamino,alkoxycarbonylalkylamino, sulfoalkylamino, alkylsulfamoylaklylamino,oxido, hydroxy alkyl, carboxy alkylcarbonyloxy, cyanoalkyl, carbonyloxy,carboxyalkylthio, arylamino, heteroarylamino, alkoxycarbonyl,alkylcarbonyloxy, carbomoylalkoxy, cyanoalkoxy, alkoxycarbonylalkoxy,carbamoylalkoxy, carbamoylalkyl carbonyloxy, sulfoalkoxy, nitro,alkoxyaryl, halogenaryl, amino aryl, alkylaminoaryl, tolyl, alkenylaryl,allylaryl, alkenyloxyaryl, allyloxyaryl, allyloxyaryl, cyanoaryl,carbamoylaryl, carboxyaryl, alkoxycarbonylaryl, alkylcarbonyoxyaryl,sulfoaryl, alkoxysulfoaryl, sulfamoylaryl, and nitroaryl.

EXPERIMENTAL SECTION I

Synthesis

Synthesis of MTL 7-3, and MTL J-1

Step A: Preparation of p-N,N-dimethylaminobenzoyl chloride ##STR219##

In a round bottom flask fitted with a reflux condenser is placed 4 g ofp-dimethylaminobenzoic acid and 8 ml of oxalylchloride. The evolution ofgas starts immediately and the spontaneous reaction is run at roomtemperature for 15 minutes. 8 ml of toluene is added and and the mixtureis heated to gentle reflux for one hour. The reaction mixture is thendistilled to dryness under reduced pressure to produce a blue-greensolid which is washed with ether and dried on a watch glass.

Step B: Preparation of p-dimethylaminobenzanilide ##STR220##

A solution of 0.95 g of aniline in 10 ml of dry ether containing 2.2 gof K₂ CO₃ was heated to reflux temperature. To the refluxing mixture 2 gof p-dimethylaminobenzoyl chloride was added as a powder slowly throughthe condenser port. The reaction was refluxed for 1.5 hours and theether distilled off. Cold water was added to the residue and thep-dimethylaminobenzanilide collected by filtration. Yield 1.51 gorange-red powder. Anilide functionality confirmed by IR.

Step C: Preparation of p-N,Ndimethyl-p-N-ethyl-N-2-chloroethylbenzophenone. ##STR221##

1.5 g of dry, powdered p-dimethylbenzanilide, 2.4 g ofN-ethyl-N-2-chloroethylaniline, and 1.3 ml of phosphorus oxychloridewere mixed in a 25 ml 2-necked flask, fitted with a thermometer immersedin the reaction mixture and a reflux condenser having a CaCl₂ dryingtube on top. The reaction was warmed slowly until an exothermic reactionoccured. The temperature was maintained at less than 100 ° C. byperiodic immersion of the flask in ice water. The reaction was thenmaintained at 95 C. for one hour to yield a dark green liquid. Thereaction mixture was then hydrolyzed in a 150 ml beaker with theaddition of a solution of 1.36 ml of concentrated HCl to 10.4 ml ofdistilled H₂ O. The beaker was covered with a watch glass and heated ona hot water bath for 1.5 hours to yield a green-yellow solution. 10:1cold water was added to the hydrolyzed mixture to form a brilliantpurple solution which was filtered. The filtered product was dissolvedin a minimum volume of ethanol, and twice the volume of cold H₂ O wasadded. The ketone was then extracted in an equal volume of chloroformwhich was removed by distillation to dryness under reduced pressure.Brilliant purple solid product. Ketone confirmed by IR and NMR.

Step D: Preparation of1-(4-N,N-dimethylaminophenyl)-1-(4-N-ethyl-N-2-chloroethylphenyl)ethylene. ##STR222##

One ml of a 3 molar etherial solution of magnesium bromide wasevaporated almost to dryness under reduced pressure in a 50 ml threenecked flask equipped with a thermometer and nitrogen sparger. The greymoist solution was suspended in 1.3 ml of dry benzene. The flask wasthen equipped for refluxing by the addition of a condenser fitted with aCaCl₂ drying tube and an addition funnel. 0.017 moles of the ketonedissolved in 4.4 ml of boiling benzene was then placed in an additionfunnel and added dropwise to the warmed methyl magnesium bromide-benzeneslurry over a half hour period. The resulting solution was refluxed forone hour. The completion of the reaction was evident by the color changeof the solution from brilliant purple to blue. The reaction mixture wascooled to room temperature, and 0.785 ml of saturated NH₄ Cl wascautiously added. Additional NH 4Cl was added until two layers wereapparent with the blue alcohol product in the bottom H₂ O layer.1.7×10⁻³ g of p-toluenesulphonic acid was added, and the solution wasboiled on a water bath with the addition of benzene until theevaporation of H₂ O was complete and only the benzene layer remained.The acid contained in the reaction mixture was then removed by theaddition of 0.73×10⁻³ g of sodium bicarbonate. The solvent was reducedto dryness under reduced pressure to yield light blue crystals.

Step E: Preparation of a perchlorate of1,5-di-(p-N-2-chloroethyl-N-ethylaminophenyl)-1,5-bis-(p-N,N-dimethylaniline)-1,3-pentadiene.##STR223##

A mixture of 8.7×10⁻⁴ moles of1-(4-N,N-dimethylaminophenyl)-l-(4-N-2-chloroethyl-N-ethylaminophenyl)ethylene,0.13 ml of ethyl orthoformate, and 0.39 ml of acetic anhydride wastreated with a solution of 0.035 ml of 72 percent perchloric acid and0.35 ml of acetic acid previously cooled to 0 ° C. The resulting mixturewas allowed to stand at room temperature for 8 days, after which time itwas treated with 0.22 ml of ether and kept an additional day at roomtemperature. The condensation product was washed with acetic acid,ethanol, and ether. The pale blue-green crystals were dissolved in aminimum volume of warm dry ethanol. The solution was centrifuged topellet a white precipitate. The dark blue supernatant solution wasremoved and distilled to dryness under reduced pressure. The bluecrystals where placed on watch glass and placed in the dark. Thestructure of the condensation compound was confirmed by IR and NMR.

Step F: Preparation of 1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisolminol)-N-ethylaminophenyl)-1,5-bis-(p-N,N-dimethylaniline)-1,3-pentadiene.##STR224##

5 mg (1.8 ×10 moles) of N-(4-aminobutyl)-N-isoluminol was suspended in0.1 ml of pyridine small test tube. 30 mg (3.6 ×10 5 moles) of thepentadiene was dissolved in 0.5 ml of pyridine and 0.25 5 ml of DMSO.This latter solution was added dropwise to the former while vigorouslystirring at room temperature initially then with intermittant imersionin a water bath at 35 ° C. The isoluminol which was only slightlysoluble in pyridine went into solution as the reaction progressed. Thereaction mixture was stirred and intermittantly immersed in the waterbath at 35 C. until the reaction was complete. This reaction and allsubsequent reactions were protected from direct light.

Step G: Preparation of Luminide, MTL 7-3(2,6-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-2,6-bis-(p-N,N-dimethylanilino)-3,5-hexadinenitrile).##STR225##

5 mg of solid KCN and 1 ml of distilled H₂ O were added to the blue-greysolution of1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-1,5-bis-(p-N,N-dimethylanilino)-1,3-pentadienein pyridine/DMSO solvent. The solution was acidified by addition ofsulphuric acid and the evolving HCN gas was removed by evaporating thesolvent to dryness under reduced pressure. The pale green crystals wereredissolved in DMSO to yield a pale green liquid. IR and NMR confirmedthe structure.

Step H: Preparation of Luminide MTL J-1(5-phosphonoformate-1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-1,5-bis-(p-N,N-dimethylaniline)-1,3-pentadiene).##STR226##

MTL J-1 was prepared by the equimolar addition of disodiumphosphonoformate dissolved in H₂ O to a DMSO solution of1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-1,5-bis(p-N,N-dimethylaniline)-1,3-pentadiene such that the final solvent was 4:3 DMSO/H ₂ O. The reactionmixture was protected from light, and the colorless reaction productsolution was packaged in light protecting vials and refrigerated at 4 °C.

Methods of synthesis of triphenylmethane dyes appear in Appendix I.

Methods of synthesis of polymethine dyes appear in Appendix II.

Methods of synthesis of azo and diazopolymethine dyes appear in AppendixIII and IV, respectively.

Methods of synthesis of quaternary ammonium salt poly methines appear inAppendix V.

Methods of synthesis of the intermediates, tetramethylortho carbonateand substituted ethylenes appear in Appendix VI.

Methods of synthesis of indoline based dyes appear in Appendix VII.

Methods of synthesis of dyes with more than one chromophore appear inAppendix VIII.

Methods of forming a leucocyanide appear in Appendix IX.

Further Exemplary Material Example 1.

The compound shown as formula 6 is prepared as follows: ##STR227##

Phenolphthalein is converted to the corresponding acid chloride bytreatment with oxalyl chloride. The acid chloride is reacted withchloromethylamine to form the corresponding amide which is in turnreacted with a dioxetan such as compound 4 to give adduct 5 wherecompound 4 is prepared from the appropriate starting dioxtene by amethod described by Schaap. The adduct 5 is converted to the finalproduct by treatment with Captopril.

Example 2.

The compound shown as formula 10 is prepared as follows: ##STR228##

Compound 7 is acylated with an acridinium ester such as compound 8 togive adduct 9 which is treated with prostaglandin E₂ to give the finalproduct 10.

Example 3.

The compound shown as formula 14 is prepared as follows: ##STR229##

Compound 11 is acylated with a biacridinium derivative such as 12 togive adduct 13 which is treated with 5-(p-sulfamylphenylazo) salicylicacid to give the final product 14.

Example 4.

The compound shown as product 18 is prepared as follows: ##STR230##

Compound 15 is reacted with the carboxylate 16 to form the ester 17where 16 is formed by linking an oxidation reduction agent such as aderivative of 2,6-dichloro phenolindophenol with a dioxene carboxylatederivative. The ester 17 is reacted with p-glycolohydroxamate to givethe final product.

Example 5.

The compound shown as formula 22 is prepared as follows: ##STR231##

Compound 19 which is formed using an appropriately substituted anilineis reacted with adduct 20 to give adduct 21 where adduct 20 is formed byalkylation of the aromatic ring of an active oxalate derivative with amolecule which can accept electrons via electron transport. Adduct 21 istreated with Baclofen to form the product 22.

Example 6.

The compound shown as formula 26 is prepared as follows: ##STR232##

Compound 23 is prepared with the appropriately substituted ethoxy groupswhich is then reacted with a phthalhydrazide such as 24 to form adduct25. The final product 26 is formed by treatment of adduct 25 withγ-aminobutyric acid.

Example 7.

The compound shown as formula 30 is prepared as follows: ##STR233##

Compound 27 is reacted with adduct 28 which is formed by akylation of anactive oxalate by a methylene blue derivative.

The product adduct 29 is treated with adenosine 3', 5'-cyclicmonophosphate to yield the final product 30.

Example 8.

The compound shown as formula 34 is prepared as follows: ##STR234##

Compound 31 is acylated with an active oxalate such as 32 to yieldadduct 33. Adduct 33 is treated with Ridavirin to yield the finalproduct 34.

Example 9.

The compound shown as formula 38 is prepared as follows: ##STR235##

Compound 35 is reacted with an alkyl halide derivatived active oxalatesuch as 36 to give adduct 37 which is treated with phosphonoacetate togive the final product 38.

Example 10.

The compound shown as formula 42 is prepared as follows: ##STR236##

Compound 39 is prepared using the proper chloromethyl substitutedbenzene and reacted with a dioxene derivative such as 40 to yield adduct41. Adduct 41 is treated with U-7130 to give the final product 42.

Example 11.

The compound shown as formula 47 is prepared as follows: ##STR237##

Compound 43 is dehydrated and treated with an indole ketone derivativedioxene such as 44 to give intermediate adduct 45 which is hydrolyzed tothe ketone adduct 46. Adduct 46 is treated withN-(phosphonacetyl)-L-asparate to yield the final product 47.

Example 12.

The compound shown as formula 51 is prepared as follows: ##STR238##

Compound 48 is prepared from the proper chloromethyl, naphthalene andreacted with a phthalhydrazide such as 49 to give adduct 50 which isreacted with trans-4-aminocrotonic acid to give the final product 51.

Example 13

The compound shown as formula 56 is prepared as follows: ##STR239##

Compound 52 is reacted with p-toluene sulfonyl chloride to give tosylateadduct 52 which is reacted with an active oxamide that has an alcoholicfunction such as 54 to give ether adduct 55. The adduct 55 is reactedwith compactin to give the final product 56.

Example 14.

The compound shown as formula 62 is prepared as ##STR240##

Compound 57 is reacted with Mg to form the Grignard reagent 58 which isreacted with a dioxene indole derivative with an aldehyde or ketonefunctionality such as 59 to give the alcohol 60. Adduct 60 is reactedwith 4-amino-hex-5-enoic acid, 61, to give the final product 62.

Example 15.

The compound shown as formula 67 is prepared as follows: ##STR241##

The compound 63 is reacted with an acid halide such as 64 to give adduct65. The acid halide 64 is prepared from the corresponding acid byreaction with oxalyl chloride. The original acid is prepared by reactinga phenazine possessing an alkyl halide and a carboxylic acid functionwith an indole derivative that has a amino group. The adduct amide 65 isreacted with but-3-ynoyl-CoA, 66, to give the final product 67.

Example 16.

The compound shown as formula 71 is prepared as follows: ##STR242##

The aldehyde compound 68 is reacted with a phosphonium ylid of aubiquinone nucleus linked to a indole dioxene derivative such as 69 toform adduct ethylene 70. (The ylid 69 is formed by an acylation reactionof an indole derivative dioxene with a ubiquinone adduct followed byreaction with triphenylphosphine.) The adduct 70 is reacted withDL-2-hydrazino-α-methyldopa to form the final product 71.

Example 17.

The compound shown as formula 76 is prepared as follows: ##STR243##

The alkylchloride 72 is reacted with alkyl amine Lophine derivate 73 toyield adduct 74 which is reacted with disodium cromoglycate, 75, to formthe final product 76.

Preparations and Routes of Administration of Luminides

Luminides can be administered orally, intramuscularly or intraveneously.

Medicinal formulations which contain one or more Luminide compounds asthe active compound can be prepared by mixing the Luminide (s) with oneor more pharmacologically acceptable excipients or diluents, such as,for example, fillers, emulsifiers, lubricants, flavor correcting agents,dyestuffs or buffer substances, and converting the mixture into asuitable galenic formulation form, such as, for example, tablets,dragees, capsules or a solution or suspension suitable for parenteraladministration. Examples of excipients or diluents which may bementioned are tragacanth, lactose, talc, agar - agar, polyglycols,ethanol and water. Suspensions or solution in water can preferably beused for parenteral administration.

Also, Luminides can be prepared as sterile lyophilized powder to which asterile solvent such as water or dimethylsulfoxide is added. Luminidesare also prepared as a sterile lyophilized powder containingdeoxycholate to effect a colloidal dispersion of insoluble Luminide.These preparations are administered as injectables includingintramuscular and intravenous administration.

Topical Luminides can be prepared as a cream, lotion, gel, and ointment.

It is also possible to administer the active compounds as such withoutexcipients or diluents, in a suitable form, for example in capsules.

Luminides can be packaged employing the usual sorts of precautious whichthe pharmacist generally observes. For example, the preparations may bepackaged in light protecting vials and may be refrigerated if necessary.

EXEMPLARY LUMINIDE PHARMACEUTICALS

Prostaglandins possess potent renal, cardiac, hemodynamic, and otherphysiological effects; however, the free agents are 95% inactivatedduring one passage through the pulmonary circulation and are essentiallyeliminated in 90 seconds from intravascular injection. A luminide whichis resistant to intravascular inactivation comprising a C functionalityof prostaglandin A₁ A₂ B₁ E₁ , E₂ or an analogue which possesses avasodilatory effect on coronary arteries and other human vascular bedsis an agent for the treatment of ischemic heart disease and is aantihypertensive agent with a long halflife. A luminide which isresistant to intravascular inactivation comprising a C functionality ofpostaglandin E, F, A or an analogue which possesses a positive cardiacinotropic effect is an inotropic agent with a long halflife. A luminidewhich is resistant to intravascular inactivation comprising a Cfunctionality of prostaglandin A, E, or an analogue prostaglandin whichpossesses natriuretic and diuretic activity is a diuretic agent with along halflife. A luminide which is resistant to intravascularinactivation comprising a C functionality of prostaglandin A, G, E₁, E₂or an analogue such as 15(S)-15-methyl PGE 2 methylester, 16,16-dimethylPGE₂,. . . AY-22,093, AY. . .22,469, AY-22,443, or 15(R)-15-methyl PGE₂which inhibits gastric acid secretion is an agent for the treatment ofpeptic and duodenal ulcer disease with a long halflife. A luminide whichis resistant to intravascular inactivation comprising a C functionalityof prostaglandin D₂, E₁ or an analogue which inhibits plateletaggregation is an antithromboembolic agent with a long halflife. Aluminide which is resistant to intravascular inactivation comprising a Cfunctionality of prostaglandin E₁, E₂ or an analogue which causesbronchial dilatation is an agent for the treatment of asthma andallergic and hypersentivity reactions with a long halflife. A luminidewhich is resistant to intravascular inactivation comprising a Cfunctionality of prostaglandin F2 or an analogue which causes abortionby luteolysis is an agent for therapeutic abortion with a long halflife.A luminide which is resistant to intravascular inactivation comprising aC functionality of prostaglandin A₂, E₁, E₂, or an analogue whichinduces erythropoiesis by stimulating the release of erythropoietin fromthe renal cortex is an agent for the treatment of anemia. A luminidewhich is resistant to intravascular inactivation comprising a Cfunctionality of prostaglandin E or an analogue which modulates Tlymphocytes to decrease their ability to reject an allogenic graft is anagent to prolong allograft survival.

A cellular permeant luminide comprising a C functionality of cellularimpermeant 2'-isopropyl-4'-(trimethylammonium chloride)-5'-methylphenylpiperidine -1-carboxylate (Amo 1618) which inhibits the cyclization oftrans-geranyl-geranyl-PP to copalyl-PP during Kaurene synthesis is afungicidal agent.

A cellular permeant luminide comprising a C functionality of cellularimpermeant adenosine cyclic 3', 5'-monophosphate or an analogue whichinhibits the release and formation of phlogistic mediators such ashistamine and kinins is an agent for treating asthma andhypersensitivity and anaphylactic reactions.

A cellular permeant luminide comprising a C functionality of cellularimpermeant 4'-sulfamylphenyl

2-azo -7-acetamid-1-hydroxynaphthalene-3,6-disulfonate (Neoprontosil),4'-sulfamyl-2, 4-diaminoazobenzene (Prontosil), or5-(p-sulfamylphenylazo) salicylic acid (Lutazol) which possess potentcarbonic acid anhydrase inhibition is a diuretic agent.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant analogue of S-adenosyl homocysteine or sinefungin is anoncostatic agent.

A cellular permeant luminide comprising a C functionality of thecellular impermeant phosphoglycolohydroxamate which inhibits Class IIaldolases present in bacterial and fungi and is noninhibitory of Class Ialdolases present in animals is an antibacterial and antifungal agent.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant inosine analogue such as formycin B which inhibits nucleotidephosphorylase during nucleotide metabolism is an agent for disorders ofpurine metabolism such as gout, is an agent that alters the toxicityand/or antitumor behavior of other analogue-containing nucleosides suchas 6-thioguanosine or 6-mercaptopurine ribonueleoside, and is animmunosuppressive agent by disruption of purine metabolism.

A cellular permeant luminide comprising a C functionality of cellularimpermeant phosphonoformate (Foscarnet) which inhibits the HIV reversetranscriptase enzyme is an agent for the treatment of acquiredimmunodeficiency syndrome. The synthesis and the results of treatment ofC3H mice infected with Raucher Spleen Focus Forming Virus with MTL J-1,a cellular permeant luminide comprising a C functionality ofphosphonoformate, is given in Experimental Secions 1 and 3,respectively.

A cellular and blood-brain barrier permeant luminide comprising a Cfunctionality of cellular and blood brain-barrier impermeantγ-amino-butyric acid (GABA) which is the major inhibitoryneurotransmitter in the mannalian central nervous system or comprising aC functionality of a cellular and blood-brain barrier impermeantinhibitor of the GABA-degrading enzyme, GABA: 2-oxoglutarateaminotransferase such as gabaculine,N-(5'-phosphopyridoxyl)-4-aminobutyric acid, ethanolamine -o-sulfate,γ-vinyl GABA, or γ-acetylenic GABA; or comprising a C functionality of acellular and blood-brain barrier impermeant compound which enhances GABArelease such as Baclofen is an anti-convulsant, muscle relaxant,sedative, and anxiolytic agent.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant oligonucleotide which binds to RNA or DNA and blockstranscription or translation of HIV or P-glycoprotein gene products isan agent for the treatment of AIDs and chemotherapeutic drug,resistance, respectively.

A blood-brain barrier permeant luminide comprising a C functionality ofblood-brain barrier impermeant adenosine which binds to brain purinergicreceptors to suppress opiate withdrawal is an agent for the managementof opiate withdrawal syndrome.

A slowly releasing peripherally acting luminide comprising a Cfunctionality of adenosine which causes coronary vasodilatation is along acting agent for the treatment of ischemic heart disease.

A cellular permeant luminide comprising a C functionality of cellularimpermeant 3-hydroxy-3-methylglutarate, 3-hydroxybutyrate,3-hydroxy-3-methylpentanoate, 4-bromocrotonyl-CoA, but-3-ynoyl-CoA, pent-3-ynoyl-CoA, dec -3-ynoyl-CoA, ML-236A, ML-236B (compactin), ML-236C,mevinolin, mevinolinic acid, or a mevalonic acid analogue which is aninhibitor of 3-hydroxy -3-methylglutaryl-CoA reductase which catalyzesthe rate-limiting and irreversible step of cholesterol synthesis whereinhibition at this step does not lead to the accumulation ofnonmetabolizable precursors is an anticholesterol agent.

A cellular permeant luminide comprising a C functionality of cellularimpermeant thioinosinate which suppresses T lymphocytes is animmunosuppressant agent.

A cellular permeant luminde comprising a C functionality of cellularimpermeant Suramin, which is a powerful inhibitor of energy drivencalcium uptake by the sarcoplasmic reticulum and is an intracellularinhibitor of Na⁺ -K⁺ ATPase where both activities increase intracellularcalcium concentrations with a concomitant inotropic effect is a cardiacinotropic agent.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant norepinephrine N-methyltransferase inhibitor such as2,3-dichloro-α-methylbenzylamine, 2,3-dichlorobenzylamine,2,3-dichlorobenzamidine, or 3,4-dichlorophenylacetamidine is a specificepinephrine action blocking agent.

A cellular permeant luminide comprising a C functionality of cellularimpermeant adenosine cyclic 3', 5'-monophosphate or a cAMP analoguewhich blocks the synthesis of fatty acids and cholesterol in the liveris an antilipidemic agent.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant inhibitor of dihydroxyphenylalanine decarboxylase during thesynthesis of epinephrine and norepinephrine such as psitectorigenin,genistein, 3', 4',5,7-tetrahydroxy-8-methylisoflavone, orbol,8-hydroxygenistein, 3',5,7-trihydroxy-4',6-dimethylisoflavone,3',5,7-trihydroxy-4',8-dimethoxyisoflavone,D,L-B-(5-hydroxy-3-indolyl)-α-hydrazinopropionic acid,D,L-α-hydrazino-α-methyldopa, D,L-B-(3-indolyl), -α-hydrazinopropionicacid, a derivative of phenylalanine such as N-methyl-3,4-dopa,α-acetamido-3,4-dimethyoxycinnamic acid, DL-α-methyl-3,4-dopa,α-methyl-B-(3-hydroxy-4-methoxyphenyl)alanine, α-methyl-3,4-dimethoxyphenylalanine, or d-catechin; D,L-B-(3-indolyl)-α-methyl-α-hydrazinopropionic acid (R)-33,4-dihydroxyphenyl!-1-fluoropropylamine, (S)-α-fluoromethyldopa,(S)-α-fluoromethyltyrosine, 5-(3,4-dihydroxycinnamoyl) salicylic acid,3-hydroxycinnamic acid, caffeic acid, 3-mercaptocinnamic acid,α-methyl-3-hydroxycinnamic acid, α-ethyl-3-hydroxycinnamic acid,3-hydroxy-w-nitrostyrene, 3,4-dihydroxyhydrocinnamic acid,3-hydroxybenzalacetone, 3-hydroxychalone, 3-hydroxybenzal furanylketone, 3-hydroxybenzal thiophenyl ketone, 3',4'-dihydroxyflavone,8-O-glucoseflavone, flavone, 3-hydroxyphenyl pyruvic acid,3,4-dihydroxyphenylpyruvic acid phenylthiopyruvic acid,4-hydroxyphenylpyruvic acid, dithiosalicyclic acid,1-hydroxy-2-naphthoic acid, 3-hydroxy-7-sulfo-2-naphtholic acid,3,5-dihydroxy-2-naphtholic acid, 4-chlorocinnamic acid, 2-chlorocinnamicacid, 2,4-dichlorocinnamic acid, 3-nitrocinnamic acid,3,5-dibromo-2-hydroxycinnamic acid, 2,4,6-triiodo -3-hydroxycinnamicacid, 2-hydroxy-4'-cyanochalone, 4-(4-hydroxycinnamoyl) benzylnitrile,2-(4-hydroxycinnamoyl)-1,4-dihydroxybenzene, quercetin-6'-sulfonic acid,5-(2-hydroxy-3,5-dibromocinnamoyl) salicylic acid or5-(3-hydroxycinnamoyl) salicylic acid is an antihypertensive agent.

A sperm permeant luminide comprising a C functionality of spermimpermeant, inhibitors of acrosin, a proteolytic enzyme located in theacrosome of sperm, such as tosyl lysine chloromethyl ketone,N-α-tosyl-L-arginine chloromethyl ketone, or ethyl p-guanidinobenzoateis a contraceptive agent.

A cellular permeant luminide comprising a C functionality of cellularimpermeant adenosine cyclic 3',5'-monophosphate (cAMP), N⁶ , O²-dibutyryladenosine cyclic 3',5'-monophosphate or an analogue whichproduces an inotropic response is a cardiac inotropic agent.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant adenosine kinase enzyme inhibitor such as 6,6'-dithiobis(9-B-D-ribofuranosylpurine) is a chemotherapeutic agent and animmunosuppressive agent.

A mitochondrial and blood-brain barrier permeant luminide comprising a Cfunctionality of a mitochondrial and blood-brain barrier impermeantinhibitor of monoamine oxidase such as phenylhydrazine,phenylethylidenehydrazine, isopropyihydrazine, or iproniazid is anantidepressant.

A cellular and blood-brain barrier permeant luminide comprising a Cfunctionality of a cellular and blood-brain barrier impermeant inhibitorof catechol-o-methyltrasferase such as 3,5-diiodo-4-hydroxybenzoic acid,S-3'-deoxyadenosylL-homocysteine, pyrogallol, R04-4602, gallic acid,3,5-dihydroxy-4-methylbenzoic acid, 1,3-dihydroxy-2-methoxybenzene,1-hydroxy-2,3-dimethoxybenzene, 2-hydroxy-1,3-dimethoxybenzene,1,3-dihydroxy-4-methoxybenzene, catechol, 3,4-dihydroxybenzoic acid,caffeic acid, 5,6-dihydroxyindole, noradnamine, dopacetamide, H 22/54,quercetin, nordihydroguaiaretic acid, U-0521, arterenone,methylspinazarin, MK 486, dopa, papaveroline, isoprenaline,7,8-dihydroxy-chlorpromazine, 3-hydroxy-4-pyridone,tetrahydroi-soquinoline pyridoxal 5'-phosphate, iodoacetic acid,3-mercaptotyramine, dehydrodicaffeic acid dilactone, methylspinazorin,3',5,7-trihydroxy-4',6-dimeth-oxyisoflavone,3',5,7-trihydroxy-4',8-dimeth-oxyisoflavone,6,7-dihydromethylspinazarin, S-adenosylhomocysteine,S-tubercidinylhomocysteine,3',8-dihydroxy-4',6,7-trimethoxyisoflavone,7-O-methylspi nochrome B,6-(3-hydroxybutyl)-7-O-methylspinachrome B, 3,5-diiodosalicyclic acid,or pyridoxal-5'-phosphate is an antidepressant agent which increasesbrain levels of monoamines and is an agent to block the metabolism ofL-dopa administered for the treatment of Parkinsonism.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant inhibitor of adenosine deaminase which blocks the metabolismof adenosine such as coformycin, arabinosyl-6-thiopurine,6-methylthioinosine, 6-thioinosine, 6-thioguanosine, N¹-methyladenosine, N⁶ -methyladenosine, 2-fluorodeoxyadenosine,2-fluoroadenosine, inosine, 2'-deoxyinosine, deoxycoformycin,1,6-dihydro-6-hydroxymethyl purine ribonucleoside,erythro-9-(2-hydroxy-3-nonyl)adenine, or9-B-D-arabinofuranosyl-6-hydroxylaminopurine is a vasodilatory agent, animmunosuppressive agent, a chemotherapeutic potentiating agent, and anagent to enhance cardiac recovery following ischemia. The mechanism inthe first case involves the accumulation of adenosine which is avasodilatory agent; the mechanism in the second case involves disruptionof purine metabolism; the mechanism in the third case involves thedisruption of the degradation of purine analogue chemotherapeuticagents; the mechanism in the fourth case involves blocking the loss ofcatabolic products of adenosine triphosphate in the form of purinenucleotides and oxypurines during ischemia. Additional luminideseffective in enhancing post ischemic cardiac recovery by the lattermechanism include those with C moietics of inhibitors of adenylatekinase, 5'-nucleotidase, and adenosine translocase such as p¹ p⁵-diadenosine pentaphosphate, α,β-methylene adenosine diphosphate, andnitrobenzyl-6-thioinosine, respectively.

A blood-brain barrier permeant luminide comprising a C functionality ofa blood-brain barrier impermeant inhibitor of Γ-aminobutyric acid uptakesuch as D,L-2,4-diaminobutyric acid, D,L-B-hydroxy GABA, (-)-nipecoticacid, trans-4-aminocrotonic acid, cis-3-aminocyclopentane-1-carboxylicacid, trans-3-aminocyclopentane-1-carboxylic acid, B-guanidinopropionicacid, homohypotaurine, 4-aminopentanoic acid, homotaurine, B-alanine,imidazoleacetic acid, 6-aminohexanoic acid, D,L-carnitine,D,L-2,6-diaminopimetic acid, D,L-2-fluoro GABA, guanidino acetic acid,2-hydrazinopropionic acid, taurine, D,L-ornithine, or sulphanilaminepotentiates the inhibitory action of GABA and is a muscle relaxant,anticonvulsant, sedative, and anxiolytic agent.

A cellular permeant luminide comprising a C functionality of cellularimpermeant inositol 1,4,5-triphosphate which is a major second messengerfor stimulating a whole range of cellular processes such as contraction,secretion, and metabolism is an agent for activating these processesincluding secretion of neural transmitters to function as an agent forthe treatment of mental disorders or secretion of insulin to function asa hypoglycemic agent.

A cellular permeant luminide comprising a C functionality of cellularimpermeant guanosine 5' cyclic monophosphate or 8-bromo guanosine 5'cyclic monophosphate which relaxes smooth muscle is an antihypertensiveand bronchodilator agent.

A cellular and blood-brain barrier permeant luminide comprising a Cfunctionality of a cellular and blood-brain barrier impermeant inhibitorof the uptake system for glycine, the inhibitory synaptic transmitter ofthe spinal cord, such as hydrazinoacetic acid is an agent for spinalreflex inhibition.

A cellular permeant luminide comprising a C functionality of a cellularimpermeant isoquinoline-sulfonamide inhibitor of protein kinase C,cAMP-dependant protein kinase, or cGMP-dependent protein kinase such asN-(2-aminoethyl)-5-isoquino-linesulfonamide is an agent which blocks thesecretion, contraction, and metabolic events regulated by thesemediators of external phydsiologic stimuli.

A cellular permeant luminide comprising a C functionality of cellularimpermeant Ribavirin which is active against HSV-1 and 2, hepatitis, andinfluenza viruses, or phosphonoacetic acid which is a highly specificinhibitor of Herpes Simplex virus induced polymerase and is activeagainst HSV-1 and HSV-2, or adenine arabinoside (ara-A), cytosinearabinoside (Ara-C), ara-A 5'-monophosphate (ara-AMP), or hypoxanthinearabinoside (ara-Hx) which is active against HSV or phagicin which isactive against vaccinia and HSV, or 4-fluoroimidazole,4-fluoroimidazole-5-carboxylic acid, 4-fluoroimidazole-5-carboxamide,5-fluoro-1-B-D-ribofurano- sylimidazole-4-carboxamide,5-amino-1-B-D-ribofuranosyl- imidazole-4-carboxamide, poly (I)·poly (C),sinefungin, iododeoxyuridine, 9-(2-hydroxy-ethoxymethyl) guanine,gliotoxin, distamycin A, netropsin, congocidine, cordycepin,1-B-D-arabinofuranosylthymine, 5,6-di-hydroxy-5-azathymidine,pyrazofurin, toyocamycin, or tunicamycin is an antiviral agent.

A cellular permeant luminde which comprises a C functionality of acellular impermeant inhibitor of fungal chitin synthetase such aspolyoxin D, nikko-mycin Z, or nikkomycin X; or which comprises a Cfunctionality of an impermeant antifungal agent such as ezomycin A₁, A₂,B₁, B₂, C₁, C₂, D₁, or D₂ or platenocidin, septacidin, sinefungin,A9145A, A9145C, or thraustomycin is an antifungal agent.

A blood-brain barrier permeant luminide comprising a c functionality ofa blood-brain barrier impermeant inhibitor of central nervous systemcarbonic anhydrase such as methazolamide, or 2-benzoylimino-3-methyl-Δ⁴-1,3,4-thiadiazoline-5-sulfonamide subsgituted at the benzolyl groupwith 3,4,5-trimethoxy, 2,4,6-trimethoxy, 2,4,5-trimethoxy, 4-chloro,4-bromo, 4-iodo, or hydrogen is an anticonvulsant agent.

A cellular and blood-brain barrier permeant luminide comprising a Cfunctionality of a cellular and blood-brain barrier impermeant inhibitorof dopamine-B-hydroxylase during the synthesis of norepinephrine andepinephrine such as fuscaric acid, 5-(3',4'-dibromobutyl)picolinic acid,5-(3'-bromobutyl) picolinic acid, 5-(3',4'-dichlorobutylpicolinic acid,YP-279, benxyloxyamine, p-hydroxybenzyloxyamine, U-21,179, U-7231,U-6324, U-0228, U-5227, U-10,631, U-10,157, U-1238, U-19,963, U-19,461,U-6628, U-20,757, U-19,440, U-15,957, U-7130, U-14,624, U-22,996,U-15,030, U-19,571, U-18,305, U-17,086, U-7726, dimethyldithiocarbamate,diethyldithiocarbamate, ethyldithiocarbamate, 2-mercaptoethylguanidine,thiophenol, 2-mercaptoethylamine, 3-mercaptopropylguanidine, 3-mercap-toprbpyl-N-methylguanidine, 2-mercaptoethanol,2-mercaptoethyl-N-methylguanidine, 2-mercaptoethyl-N,N'-dimethylguanidine, 4,4,6-trimethyl-3,4-dihydropyrimidine-2-thiol,N-phenyl-N'-3-(4H-1,2,4-trizolyl)thiourea, methylspinazarin,6,7-dimethylspinazarin, 7-O-methy-spinochrome B,6-(3-hydroxybutyl)-7-O-methylspinachrome B, aquayamycin, chrothiomycin,frenoclicin, N-n-butyl-N'-3-(4H-1,2,4-trazolyl) thiourea,propylthiouracil, mimosine, mimosinamine, or mimosinic acid is anantihypertensive agent.

A cellular permeant luminide of a cellular impermeant inhibitor ofhistidine decarboxylation during the synthesis of histamine such as ²-hydroxy-5-carbomethoxybenzyloxyamine, 4-toluene-sulfonic acidhydrazide, 3-hydroxy benzyloxyamine, hydroxylamine, aminooxyacetic acid,4bromo-3-hydroxybenzyloxyamine (NSD-1055), rhodanine substituted in the3 position with p-chlorophenethyl, p-chlorobenzyl, p-methylthiobenzyl,p-methylbenzyl, p-fluorobenzyl, amino, 3,4-dichlorobenzyl,p-bromobenzyl, p-methoxybenzyl, p-bromoanilino, p-iodoanilino,p-chloroanilino, p-toluidino, anilino, 2,5-dichloroanilino,dimethylamino, or p-methoxyphenyl;2-mercaptobenzimidazole-1,3-dimethylol, 4-bromo-3-hydroxy -benzoic acid,4-bromo-3-hydroxybenzyl alcohol, 4-bromo-3-hydroxy-hippuric acid,(R,S)-α-fluoromethyl- histidine, (S)-α-fluoromethylester, L-histidineethyl ester, L-histidinamide, D,L-3-amino-4-(4-imidazolyl)-2-butanone,2-bromo-3-hydroxybenzyloxyamine, 5-bromo-3-hydroxybenzyloxyamine,4,6-dibromo-3-hydroxybenzyloxyamine, aminooxypropionic acid,benzyloxyamine, 4-bromo-3-benzenesulfonyloxybenzyloxyamine,3',5,7-trihydroxy-4',6-dimethoxyisoflavone, lecanoric acid,N-(2,4-dihydroxybenzoyl)-4-aminosalicylic acid, or3',5,7-trihydroxy-4',8-dimethoxyisoflavone is an agent for the treatmentof allergy, hypersensitivity, gastic ulcer, and inflamation.

Luminides also comprise C functionalities of pharmaceutical molecules asappear in Physicians Desk Reference, Edward R. Barnhart, 41th ed., 1987,Medical Economics Company Inc., N.J.; USAN and the Dictionary of DrugNames, ed. by Mary C. Griffiths, The United States PharmacopedialConvention, (1986); and The Pharmacological Basis of Therapeutics, ed.by A.G. Gilman, L. Goodman, A. Gilman, 7th ed., (1985), MacMillanPublishing Co., N.Y., N.Y., (incorporated by reference) where thepharmacokinetics and/or the pharmacodynamics of these agents are alteredvia delivery to the site of action by way of a luminide agent such thatthe therapeutic effect or therapeutic ratio is enhanced. Some examplesfollow which are not meant to be exhaustive.

A luminide with high permeance to the blood-brain barrier comprising a Cfunctionality of a centrally acting converting enzyme inhibitor such ascaptopril which possesses a lesser blood-barrier permeance is an agentwith increased efficacy of the central nervous system antihypertensiveeffect of the centrally acting converting enzyme inhibition includingcaptopril.

A luminide with an A moiety which reacts with free radicals and electroncarriers in the cytosol of bacteria to effect release of the C moietyand which possesses greater permeance or B-lactamase resistance than itsC moiety of a bacterial wall synthesis inhibitor such as a penicillin,cephalosporin, or cephamycin is a more efficacious and broad spectrumantibacterial agent than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an agent which blocks bacterialsynthesis of tetrahydrofolate such as a sulfonamide (an analogue ofp-aminobenzoic acid) including sulfanilamide, sulfadiazine,sulfamethoxazole, sulfisoxazole, or sulfacetamide or an inhibitor ofdihydrofolate reductace including pyrimethamine, cycloguanil,trimethoprin, isoaminopterin, 9-oxofolic acid, or isofolic acid is amore efficacious antibacterial than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than it C functionality of a bactericidal agent such asnalidixic acid or oxolinic acid is a more efficacious antibacterial thanthe free C moiety.

A luminide. possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an inhibitor of bacterial proteinsynthesis such as vancomycin, an aminogylcoside, erythromycin,tetracyclin, or chloramphenicol is a more efficacious antibacterialagent than the free C moiety.

A luminide prossessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an inhibitor of viral DNApolymerase such as vidarabine is a more efficacious antiviral agent thanthe free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety which is tuberculostatic ortuberculocidal such as isoniazid or aminosalicyclic acid is a moreefficacious agent for the treatment of tuberculosis than the free Cmoiety.

A luminide possessing more favorable pharmacokinetics or pharmodynamicsthan its C moiety of an anthelmintic agent such as oxamniquine,piperazine, metronidazole, diethylcarbamazine, paromomycin, niclosamide,bithionol, metrifonate, hycanthone, dichlorophen, or niclosamide is amore efficacious anthelmintic agent than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an H₂ -blocking agent such ascimetidine or ranitidine is a more efficacious anti-ulser agent than thefree C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an agent which blocks release ofnorepinephrine such as sotalol, guanethidine, pindolol, pronethalol, KO592, practolol, oxprenolol, or pronethalol is an antiarrhythmic,antihypertensive and antipsychotic agent.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of a xanthine oxidase inhibitor suchas allopurinol, thioinosinate, 5,7-dihydroxypyrazolo 1,5-a! pyrimidinesubstituted at the 3 position with hydrogen, nitro, bromo, chloro,phenyl, 3-pyridyl, p-bromophenyl, p-chlorophenyl, p-acetylanilino,p-tolulyl, m-tolulyl, naphthyl, or 3,4-methylenedioxyphenyl;8-(m-bromoacetamidobenzylthio)hypoxanthine,8-(m-bromoacetamidobenzylthio)hypoxanthine, guanine substituted at the 9position with phenyl, 4-chlorophenyl, 3-chlorophenyl,3,4-dichlorophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,4-dimethylaminophenyl, 4-aminophenyl, 3-aminophenyl,3-trifluormethylphenyl, 4-benzamido, 4-carboxylphenyl, 4-methylpheyl,4-ethylphenyl, 3-methylphenyl, B-naphthyl, or 4-ethoxyphenyl;4,6-dihydroxypyrazolo 3,4-d! pyrimidine, 4-trifluoromethylimidazolessubstituted at the 2 position with phenyl, p-chlorophenyl,p-methoxyphenyl, p-acetylanilino, p-nitrophenyl, p-dimethylaminophenyl,p-cyanophenyl, p-fluorophenyl, p-carboxyphenyl, m-chlorophenyl,3,4-dichlorophenyl, 4-pyridyl, 3-pyridyl, 2-quinolyl, 6-quinolyl,4-quinolyl, 7-quinolyl, 2-pyrazinyl, or1-(2-pyridyl-4-trifluoromethyl-5-bromoimidazolyl;5-(4-pyridyl)-1,2,4-triazoles substituted at the 5 position with4-pyridyl, 3-pyridyl, 2-pyridyl, phenyl, p-chlorophenyl, m-chlorophenyl,p-sulfonamidophenyl, 3,5-dichlorophenyl, 3,5-dicarboxyphenyl,6-quinolyl, 2-furyl, 4-pyridazinyl, 2-thienyl, 2-pyrimidinyl,4-pyrimidinyl, or 4-pyrazinyl; difunisal, 4(or5)-(2-aminoethylthio-azo)imidazole-5(or 4)-carboxamide, 4 (or5)-diazoimidazole-5(or 4)-carboxamide , or S- 5(or 4)-carbamoyl-4(or5)-imidazolyl azo! cysteine is a more efficacious agent for thetreatment of gout and hyperuricemic conditions than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety which inhibits DNA synthesis such asa bis-thiosemicarbazone, 3,5-diisopropylsalicyl- hydroxamic acid,4-hydroxybenzoylhydroxamic acid, 3-methylsalicylhydroxamic acid2,5-dihydroxybenzoylhydroxamic acid, or2-hydroxy-3,4,5-trimethoxybenzoylhydroxamic acid; or which inhibitsnucleotide synthesis such as N-(phosphoacetyl)-L-aspartate whichinhibits asparatate transcarbamylase during pyrimidine synthesis, orazaserine or 6-diazo-5-oxo-L-norleucine which inhibits purine synthesisat the phosphoribosyl-formyl-glycineamidine synthetase step; or which isan antifolate such as methotrexate,2,4-diamino-5-benxyl-6-(4-phenylbutyl) pyrimidine,2,4-diamino-5-phenyl-6-(4-phenylbutyl) pyrimidine,2,4-diamino-5-phenyl-6-(3-anilinopropyl) pyrimidine,2-amino-4-hydroxy-5-phenyl-6-(3-p-aminobenzoylglutamic acid propyl)pyrimidine, N-(p- (2,4-diamino-6-quinazolinyl)methyl!methylamino!benzoyl!-L-glutamic acid, N- p-2,4-diamino-5-methylquinazolinyl)methylamino!benzoyl!-L-aspartic acid,N- p- (2-amino-4-hydroxy-6-quinazolinyl) methyl-!methylamino!benzoyl!-L-glutamic acid, 2,4-diaminoquinazolines: CCNSC 105952, CCNSC112846, CCNSC 121346, CCNSC 122761, CCNSC 122870, CCNSC 529859, CCNSC529860, or CCNSC 529861; 8-aza GMP, 7-deaza-8-aza GMP, 2'-dGMP,B-D-arabinosyl GMP, pentopyranine A-G,B-ribofuranosyl-1,3-oxazine-2,4-dione, pyrazofurin,6-(p-chloroacetylanilinomethyl)-5-cetylvinylanilinomethyl)-5-(p-chlorophenyl)-2,4-diaminopyridine,6-(p-chloroacetyl- ethylanilino-methyl)-5-(p-chlorophenyl)-2,4-diaminopyridine,6-(p-chlorophenylbutylanilinomethyl)-5-(p-chlorophenyl)-2,4-diaminopyridine, p-(2,6-diamino-1,2-dihydro-2, 2-dimethyl- S-triazin-1-yl)phenylpropionyl sulfanilylfluoride or variants of the propionamidebridge of acrylamido, N-ethylsulfonamido, N-ethylcaboxamido,oxyacetamido, or oxythyloxy; or which inhibits purine or pyrimidinesynthesis such as xylosyladenine, 6-azauridine, 5-aminouridine,5-azaorotic acid; or which inhibits nucleotide interconversion such ashadacidin, 6-mercaptopurine, azathioprine, nitro-dUMP,psicofuranine,decoyinine, 5-fluorouracil, 5-fluorodeoxyuridine, shadowmycin; or whichinhibits nucleotide utilization such as cytosine arabinoside,arabinosyladenine; or which becomes incorporated into polynucleotidessuch as 8-azaguanine, tubercidine, toyocamycin, sangivamycin, formycin,7-deazainosine, 8-azainosine, or 7-thia-7, 9-dideazainosine; or which isa glyoxalase inhibitor such as Glyo-I, or Glyo-II, is a more efficaciousantineoplastic agent than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an agent which blocks synthesis ofprostaglandin A₂ which effects platelett aggregation such as salicylicacid, pyrogallol, 5,8,11,14-eicosatetraynoic acid, α-naphthol, guaiacol,propylgallate, nordihydroguiaretic acid, N-0164, benzydamine,9,11-azoprosta-5, 13-dienoic acid, 2-isopropyl-3-nicotinylindole, is amore efficacious antithrombotic agent than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an agent wnich blocksprostaglandin synthetase such as indomethacin, sulindac, tolmetin,mefenamic acid, ibuprofen, naprozen, fenoprofen, fluribiprofen,ketoprofen, meclofenamic acid, flufenamic acid, niflumic acid,benzydamine, oxyphenbutazone, asprin, acetaminophen, salicylamide,O-carboxydiphenylamine, tolectin, diclofenac, 2,7-dihydroxynaphthalene,5-(4-chlorobenzoyl)-1-methylpyrrole-2-acetic acid,5-(4-methylbenzoyl)-1,4-dimethylpyrrole-2-acetic acid,5-(4-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid,5-(4-fluorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid,5-(4-chlorobenzoyl)-1,4-dimethylpyrrole-2-(2-propionic acid),5,6-dehydroarachidonate, 11,12-dehydroarachidonate, or5,8,11,14-eicosatetraynoate; or of an agent which blocks lipoxygenase orblocks leukotriene action such as BW755C, FPL 55712, or U-60,257 is amore efficacious nonsteroidal anti-inflammatory agent than the free Cmoiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an antiarrhythmic agent such asprocainamide or quinidine is a more efficacious antiarrhythmic agentthan the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an inhibitor of hepatic synthesisof Vitamin K dependent clotti-ng factors such as warfarin sodium,dicumarol, 4-hydroxycoumarin, phenprocoumon, or acenocoumarol is a moreefficacious anticoagulant than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety which directly relaxes vascularsmooth muscle such as hydralazine, minoxidil, or isoxsuprine is a moreefficacious antihypertensive agent than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of a Na⁺ -K⁺ -ATPase inhibitor suchas digtoxigenin, digoxigenin, cymarol, periplogenin, or strophanthidiol,or ouabain glycosides, cardenolides, or basic esters, or ICI-63,632,ICI-63,605, ICI-62-655, ICI-62,838, ICI-69,654, ICI-58,622, ICI-61,374,ICI-57,267, ICI-61,424, ICI-61,411, ICI-65,199, ICI-70,898, ICI-70,899,ICI-70,900, ICI-70,901, ICI-62,966, ICI-65,210, ICI-63,116, ICI-62,936,ICI-65,551, ICI-63,978, ICI-62,276, ICI-63,056, ICI-67,135, ICI-67,167,ICI-67,134, ICI-67,875, ICI-67,880, or ICI-61,558 is a more efficaciousinotropic agent than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety which is a calcium channel blockersuch as prenylamine, verapamil, fendiline, gallopamil, cinnarizine,tiapamil, diltiazem, bencyclan, or nifedipine; or an agent whichstabalizes calcium binding to cellular calcium stores and therebyinhibits the release of this calcium by contractile stimuli such as8-(N,N-diethylamino)-octyl 3,4,5-trimethoxybenzoate (TMB-8) is a moreefficacious vasodilatory agent than its free moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of a monoamine oxidase inhibitor suchas tranylcypromine, phenylethylamine, trans-cinnamic acid, phenelzine,or isocarboxazid is a more efficacious antidepressant agent than thefree C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of a benzodiazepine compound such asclorazepate is a more efficacious tranquillizer than the free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an antiseizure agent such asvalproic acid is a more efficacious antiepileptic agent than the free Cmoiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of an agent which causes repressionof the synthesis of HMG-COA reductase such as 20-α-hydroxycholesterol,22-ketocholesterol, 22-α-hydroxycholesterol, 25-hydroxycholesterol,22-B-hydroxycholesterol, 7-α-hydroxycholesterol, 7-B-hydroxycholesterol,7-ketocholesterol, or kryptogenin; or of an agent which inhibits HMG-COAreductase such as, lorelco; or of an agent which inhibits lipolysis suchas 5-methylpyrazole -3-carboxylic acid (U-19425), nicotinic acid,uridine, inosine, 3,5-dimethylisoxazole (U-21221), 3,5-dimethypyrazole,prostaglandin E₂, eritadenine, or eritadenine isoamyl ester; or of anagent which inhibits lipogenesis such as ascofuranone,(-)-hydroxycitrate, or tetrolyl-CoA; or of an agent which ishypocholesterolemic such as lentysine; or of an agent which lowerstriglycerides such as lopid; or of an agent which is an inhibitor ofacetyl-CoA carboxylase during lipogenesis such as 2-methyl -2-p-(1,2,3,4-tetrahydro-1-naphthyl)-phenoxy!-propionat e (SU13437), ²-(p-chlorophenoxy)-2-methylpropionate, kynurenate, xanthurenate,kynurenine, 3-hydroxyanthranilate, or 2-methyl-2-p-(p-chlorophenyl)phenoxy! propionate; or of an agent which is aninhibitor of hepatic B-lipoprotein production such as orotic acid is amore efficacious hypolipidemic agent than its free C moiety.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics than its C moiety of a vasodilater such as WS-1228A, orWS-1228B; or of an anti-inflammatory agent such as amicomacin A is amore efficacious vasodilator or anti-inflammatory agent, respectively,than the free C moiety.

A luminide with more favorable pharmacokinetics or pharmacodynamics thanits C moiety which is a protease inhibitor such as leupeptin; or whichis an inhibitor of pepsin such as a pepstatin, a pepstanone, or ahydroxypepstatin is a more efficacious agent for the treatment ofmuscular dystrophy or peptic ulcer disease, respectively, than its freeC moiety.

A luminide with more favorable pharmacokinetics or pharmacodynamics thanits C moiety of an inhibitor of cell surface enzymes such as bestatin,amastatin, forphenicine, ebelactone, or forphenicin is a moreefficacious immunomodifier agent than its free C moiety.

A luminide with more favorable pharmacokinetics or pharmacodynamics suchas enhanced permeability relative to its C moiety of a phosphodiesteraseinhibitor such as theophyllineacetic acid, theophylline, dyphylline,disodium cromoglycate,6-n-butyl-2,8-dicarboxy-4,10-dioxo-1,4,7,10-tetrahydro-1,7-phenanthrolin,2-chloroadenosine, dipyridamole, EG 626, AY-17,605, AY-17,611,AY-22,252, AY-22,241, cis-hinokiresinol, oxy-cis-hinokiresinol,tetrahydro-cis- hinokiresinol, trans-hinokiresinol, dehydrodicaffeicacid, 2,6,4'-trihydroxy-4-methoxybenzophenone, p-hydroxyphenyl crotonicacid, papaverine, 3-(5-tetrazolyl)-thioxanthone-10,10-dioxide,3-carboxythioxanthone-10,10-dioxide, W-7, HA-558, MY-5445, OPC-3689,OPC-13135, or OPC-13013, reticulol, PDE-I, or PDE-II is a moreefficacious cardiac stimulant, diuretic, vasadilator, platelettaggregation inhibitor, .and an agent for the treatment of asthma andallergic reaction than its free C moiety. Such a luminide comprising a Cmoiety of ICI 74,917 is also a more efficacious agent for the treatmentof asthma and allergic reactions.

A luminide possessing more favorable pharmacokinetics orpharmacodynamics such as enhanced cellular or blood-brain barrierpermeability or resistance to inactivation by tissue dehalogenases andtransaminases than its C functionality of an inhibitor of tyrosinehydroxylase, the enzyme catalyzing the rate-limiting reaction in thebiosynthesis of norepinephrine, such as azadopamine,isopropylazadopamine, dimethylazadopamine; triphenolic compounds such asn-propylgallate; diphenolic benzoic acid derivatives such as3,4-dihydroxybenzoic acid; phenylcarbonyl derivatives such as3,4-dihydroxybenzaldehyde, arterenone, or adrenalone H 22/54,3-iodo-L-tyrosine, D,L-α-methyl-p-tyrosine, L-3-iodo-α-methyltyrosine,3-bromo-α-methyltyrosine, gentistic acid, 3-chloro-α-methyltyrosine,phenylalanine derivatives, 3,5-diiodo- L-tyrosine,3,5-dibromo-L-tyrosine, 3-bromo-α-methyl-L- tyrosine,3-fluro-α-methyl-L-tyrosine, catechol analogues,3,4-dihydroxyphenylethylacetamide, 3,4-dihydroxyphenyliso-proplyacetamide, 3,4-dihydroxyphenylbutylacetamide,3,4-di-hydroxyphenylisobutylacetamide, D,L-α-methylphenylalanine,D,L-3-iodophenylalanine, D,L-4-iodophenylalanine,D,L-α-methyl-3-iodophenylalanine, D,L-a-methyl-3-bromophenylalanine,D,L-α-methyl-3-chlorophenylalanine, D,L-α-methyl-3-fluorophenylalanine,mimosine, mimosinamine, mimosinic acid, 7-O-methylspinochrome B,6-(3-hydroxybutyl)-7-O-methylspinachrome B, aquayamycin, chrothiomycin,frenolicin, fuscaric acid, pentylpicolinic acid, dopstatin,methylspinazarin, 6,7-dihydroxymethylspinazarin,3-ethyl-α-methyltyrosine, 3-methyl-α-methyltyrosine,3-isopropyl-x-methyltyrosine, 3-allyl-α-methyltyrosine, 3-4-hydroxy-3-(2-methylallyl)-phenyl!-2-methylalanine,, 3-3-(2,3-epoxypropyl)-4-hydroxyphenyl!-2-methylalanine,3-isobutyl-α-methyltyrosine, 3-methylvinyl-α-methyltyrosine,5-methyl-6,7-diphenyltetrahydropterin,3-(2,3-dihydro-2,2-dimethyl-5-benzofuranyl!-2-methylalanine, 3-2,3-dihydro-2,2-dimethyl-5-benzofuranyl!-2-methylalan ine, α-methyldopa,or ethyl-3-amino-4H-pyrrolo 3,4c! isoxazole carboxylate is a moreefficacious antihypertensive agent than the free C moiety.

In addition, luminides which provide controlled extracellular release ofbiologically active substances such as drugs and proteins includingenzymes and hormones are herein disclosed as macromolecular luminides.Luminides, each comprising a C functionality of a drug or protein suchas insulin, erythropoietin, interleuken 2, interferon, growth hormone,atrial natriuretic factor, tissue plasminogen activator, ananti-inflammatory drug, an antihypertensive drug, an inotropic drug, acontraceptive drug, etc., are attached to a polymeric material to whichan enzyme is immobilized to form a macromolecular luminide. The enzymemolecules react with molecules in the ambient extracellular environmentat a rate in proportion to their concentration to produce peroxide orfree radicals which react with the A functionality molecules causingthem to achieve a high energy electronic state which is followed by therelease of the C molecules where the release of C is in proportion tothe ambient concentration of, the substrate of the enzyme.

For example, a macromolecular luminide which provides a release ofinsulin in proportion to the ambient glucose concentration comprisesluminide molecules, each comprising a C functionality of insulin,covalently bound to a biocompatible polymer to which the enzyme glucoseoxidase is immobilized. The immobilized enzyme reacts with glucose at arate proportional to the ambient glucose concentration to produceperoxide which reacts with the A functionality molecules of the attachedluminide molecules to effect release of insulin. Because the insulinrelease is in proportion to the glucose concentration thismacromolecular agent represents a very effective diabetic therapy.

As an additional example, cardiac ischemia results in the production andrelease of degradation products of purines such as xanthine. The enzymexanthine oxidase oxidizes xanthine and directly reduces oxygen tohydrogen peroxide. Furthermore, tissue plasminogen activator (TPA) is aneffective agent for the treatment of myocardial infarction because thisagent effects the lysis of fibrin clots in coronary arteries toestablish reperfusion. Cardiac recovery is enhanced by diminishing thedelay between the occlusion event and the administration of TPA. Thus, amacromolecular luminide comprising luminide molecules, each comprising aC functionality of TPA, bound to a biocompatible polymer to whichxanthine oxidase is immobilized is an agent which releases TPA inproportion to the products of cardiac ischemia. Thus, it is a highlyeffective agent to resolve myocardial infarctions.

In another embodiment, luminide molecules, each comprising an Afunctionality which achieves a high energy electronic state via areduction reaction, are attached to a conducting polymer to which anenzyme is immobilized. The immobilized enzyme oxidizes molecules in theambient environment and transfers electrons to the conducting polymerwhich reduces the A functionality molecules directly or indirectly viathe optional D functionality molecules to effect release of the Cmolecules.

In the latter embodiment, the conducting polymer derivatized with anenzyme, can be replaced with an electrocatalytic polymer which isreduced directly by molecules in the ambient environment and transfersthe electrons to the luminide molecules to effect release of the Cmolecules. For example, polyvinylferrocene and poly-N-(9,10-anthroquinone)- ethylenimine are conductive polymers andelectrocatalytically oxidize glucose. Thus, a macromolecular luminidefor the treatment of diabetes comprises a conducting polymer such aspolyvinylferrocene to which glucose oxidase is optionally bound and towhich luminide molecules are bound where the A functionality moleculesof the polymer attached luminides achieve a high energy electronic statevia a reduction reaction. The polymer is reduced when glucose oxidaseaccepts electrons from glucose and transfers them to the polymer. Or,the electrocatalytic polymer is reduced directly by glucose. The reducedpolymer reduces the A functionality molecules directly or indirectly viathe optional D functionality molecules to effect release of insulinmolecules in proportion to the ambient glucose concentration.

Furthermore, macromolecular luminides can be directed to a specificextracellular target site such as an anatomical or biologicalcompartment or organ by further attaching monoclonal antibody moleculesto the polymer of the macromolecular luminide which bind to a moleculeat the desired target site.

In addition to pharmaceutical agents, luminides also comprise pesticidesincluding. herbicides, fungicides, miticides, nematocides, fumigants,growth regulators, repellants, defoliants, rodenticides, molluscicides,algicides, desicants, antehelmintics, and bactericides. These luminidescan be obtained by one skilled in the art by combining thefunctionalities, A, B, and optionally, D, of energy donor, energyacceptor, and electron transfer functionality, respectively, with a Cmoiety which possesses pesticidal activity. C moieties include thosethat appear in Chemical Week Pesticides Register, Robert P. Ovelletteand John A. King, 1977, McGraw-Hill Book Company (incorporated byreference) and analogues of these agents. Enhanced pesticidaleffectiveness is acheived via improved delivery of these agents to theirtarget receptors by way of luminide molecules which possess desirableproperties such as increased permeance to the cells of the organismrelative the free C moieties.

EXPERIMENTAL 2

Release Reaction

MTL 7-3 was tested for release of the nitrile group as free cyanideduring the reaction of the isoluminol group with hydrogen peroxide asfollows:

1.2×10⁻⁵ moles of 1, 5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-1,5-bis-(p,N,N-dimethylaniline) -1,3-pentadiene wasreacted with an excess of cyanide in a 4/4/1 DMSO/pyridine/H₂ O solvent.The solution was acidified to pH one and distilled under vacuum untilgas no longer evolved. The product was split into six equal aliquots ofapproximately one milliliter volume. A volume of 0.1 ml of 1M NaOH wasadded to all aliquots. A volume of 0.05 ml of 3% hydrogen peroxide wasadded to 3 of the aliquots. After five minutes cyanide was assayedfollowing the proceedure of Gunther and Blinn.

This proceedure involves the addition of acid to the sample which isheated to distill hydrocyanic acid which is captured in a basic solutionto which a colorimetric reagent is added to develop a color which iscompared to a standard curve. The results are as follows:

    ______________________________________                                        Sample        Released cyanide (ug)                                           ______________________________________                                        TEST ONE                                                                      Blank         0                                                               MTL 7-3       22.2                                                            MTL 7-3/H.sub.2 O.sub.2                                                       26.4                                                                          TEST TWO                                                                      Blank         0                                                               MTL 7-3       21.5                                                            MTL 7-3/H.sub.2 O.sub.2                                                       27.0                                                                          TEST THREE                                                                    Blank         0                                                               MTL 7-3       15.0                                                            MTL 7-3/H.sub.2 O.sub.2                                                       30.5                                                                          ______________________________________                                    

The release reaction test was repeated as follows: 4.5×10⁻⁶ moles of1,5-di-(p-N-2-(N-(4-aminobutyl)-N-ethylisoluminol)-N-ethylaminophenyl)-1,5-bis-(p-N,N- dimethylaniline) -1,3-pentadienewas reacted with excess cyanide in a 1:1 DMSO/H₂ O solvent. The solutionwas acidified to ph one and was distilled for 90 minutes under reducedpressure. The volume of the solution was made 4 milliliters by additionof H₂ O. The solution was made basic by addition of 1M NaOH and wassplit into two equal volume aliquots. 0.05 milliliters of 3% H₂ O₂ wasadded to one aliquot. Both aliquots stood for 5 minutes, and thencyanide was determined as previously described. The results are asfollows:

    ______________________________________                                        TEST FOUR                                                                     Sample        Released cyanide (ug)                                           ______________________________________                                        Blank         0                                                               MTL 7-3       73.4                                                            MTL 7-3/H.sub.2 O.sub.2                                                       109. 1                                                                        ______________________________________                                    

The results indicate that cyanide was released as a result of a reactionof hydrogen peroxide with the luminide compound. The release of lesseramounts of cyanide during the control experiment is consistent with thethermochromic properties of the luminide compound at elevatedtemperatures as the samples were heated during the cyanide determinationproceedure.

EXPERIMENTAL 3

Efficacy of Treatment of C3H Mice Infected with Raucher Spleen FocusForming Virus with Luminide MTL J-1.

The effectiveness of MTL J-1 was tested in C3H mice against the virusRSFFV (Raucher Spleen Focus Forming Virus) which is a retrovirus and isa valid animal model for HIV infection by application to the aboveidentified mice according to the following procedure:

Three groups of two month old C3H mice, each comprising four animalswere provided as one control and two test groups wherein, the threegroups (I-III) were subjected to an infectious dose of RSFFV on day one.The first group (I) served as control and received no treatment. GroupII and III were treated with 10uM total body weight concentration of thedrug Foscarn.et and the test compound MTL J-1, respectively which wasadministered each day for days 5 through 9. The animals were sacrificedon day 14, where upon the spleens where removed and weighed. The resultsare summarized in the following table:

                  TABLE 1                                                         ______________________________________                                                    I            II     III                                           ______________________________________                                        Ending Weight                                                                             21.1         21.2   22.5                                          (grams)                                                                       Weight change                                                                             1.675        0.15   2.25                                          (grams)                                                                       Spleen weight                                                                             .083         .079   .068                                          Normalized                                                                    (grams)                                                                       ______________________________________                                    

The tests were redone with a second control group (IA) having noinfection of RSFFV and receiving no treatment with any drug, whereingroups I and IA comprise four mice each, and groups II and III comprisefive mice each, providing the results summarized below:

                  TABLE 2                                                         ______________________________________                                                     IA     I          II   III                                       ______________________________________                                        Ending Weight                                                                              18.5   18.6       19.6 19.2                                      (grams)                                                                       Weight change                                                                              +1.0   +1.8       +1.6 +1.5                                      (grams)                                                                       Spleen weight                                                                              0.046  0.060      0.061                                                                              0.049                                     Normalized                                                                    (grams)                                                                       ______________________________________                                    

These results indicate that MTL J-1 was nontoxic as demonstrated by anabsence of weight loss and that MTL J-1 was highly effective asdemonstrated by the absence of splenomegaly in the animals administeredthis compound.

The biologically active substances not specifically mentioned areincluded in, and functionally applicable as a drug in the compound ofthe present invention. Also, the references referred to herein or filedherewith are hereby incorporated by reference. Modifications andsubstitutions made by one of skilled in the art are considered to bewithin the scope of the present invention, which is not to be limitedexcept by the claims.

APPENDIX I

Triphenyl Methanes

Triphenyl methane dyes have been known and used for many years.Consequently many general-type syntheses have been worked out andpublished. The following four synthesis methods have been used almostexclusively for the 15 triphenyl methane dyes synthesized.

Method A. Michler's Ketone Method

To equal molar quantities of a p-amino benzophenone or di-(p-amino)benzophenone (Michler's type ketones) and aromatic amines, such asanilines and naphthyl amines, sufficient toluene-phosphorous oxychloridesolution is added (3-5) to dissolve the reactants at 50° C. Thetemperature is raised to 80° C. and the solution is stirred forapproximately 45 minutes or until the mass becomes very viscous. Thesample is cooled and 10 ml of water added for each ml of phosphorousoxychloride used, and heated to boiling. The solution is cooled andtreated with 6N sodium hydroxide solution until the pH is 8 or more. Thesample is steam-distilled to removed the last trace of any toluene orsteam volatile unreacted amine. It is cooled and the aqueous phasepoured off. The organic phase is dissolved in hot methanol-acetic acid(1:1) solution. The sodium salt of the anion for the dye form desired isthen added.

The sample is cooled and ether added slowly, while stirring to effectcrystallization of dye.

This method varies slightly from the known published methods, but hasbeen found to have several advantages for laboratory preparation of dyesof the types: ##STR244## where any one of the phenyl groups may bereplaced by a naphthyl group.

Method B. Michler's Hydrol Method Part 1.

Triphenylmethane type compounds may be produced by the condensation of adiphenyl substituted secondary alcohol and an aromatic ring. Thesecondary alcohol is of a type called Michler's hydrol of the generaltype formula: ##STR245## which is produced by the controlled reductionof the corresponding ketone with sodium amalgam in alcohol alcohol-watermixture, dried, and stored in a vacuum dessicator.

The hydrol is then condensed with the desired substituted benzene ringof the general-type formula: ##STR246## in concentrated sulfuric acidand at a temperature below 60° C. for several hours. The reactionmixture is diluted with water and the acid neutralized until thecondensation product is precipitated out. The product has thegeneral-type formula: ##STR247## Part 2

The condensation product is then oxidized with lead peroxide in anacidic-aqueous media to the general-type formula: ##STR248##

Any excess lead peroxide is neutralized with sodium carbonate. The leadis precipitated with sodium sulfate and filtered off. The acid isneutralized to a pH of 7 and the dye salted out as the chloride or asthe zinc chloride double salt.

This method was found to be useful in preparing triphenyl methane dyeswhere one of the phenyl groups is to have substituents other than anamino group.

APPENDIX II Method C. Aniline - Benzaldehyde Method

Under reflux, a two-mole quantity of an aniline and one mole of abenzaldehyde is heated with zinc chloride as a catalyst to produce thetrue leuco form of the desired dye.

A stoichiometric quantity of lead dioxide paste and hydrochloric acid isadded to a weighed quantity of the leuco dye. This is stirred for 30minutes and then filtered. Sodium sulfate is added to precipitate anysoluble lead salts, which is then filtered and the filtrate neutralized.A neutral salt is added to salt out the dye. (The salt chosen forsalting out will depend on the anion form of the dye desired.)

Method D. Alkyl Halide Method Dyes of the type ##STR249## may be reactedwith alkyl iodides in an alkaline methanol solution to replace thehydrogen on each amino group with the alkyl group of the alkyl iodide toyield dyes of the type: ##STR250## of the 15 triphenyl methan dyessynthesized, 6 were found to be phototropic and were previouslytabulated under 3.2.6.1. For the other nine dyes, no phototropic systemshave yet been developed. Polymethines

Polymethines (refs. 13, 18, 19) may be classified generally by thedegree of symmetry around the conjugated carbon chain. If we representthe polymethines by the general formula: ##STR251## we may furtherclassify the dyes on the basis of the identify of the various R groups.It is prerequisite to this family that at least two of the R groups becapable of extending the conjugation of the chain by accepting apositive charge, ##STR252## being such a group.

Where R₁ and R₄ meet the prerequisite of the family and either R₂ or R₃or both are hydrogen, the dyes may be prepared by methods I and II ofthe four general methods given in the succeeding pages.

Where R₄ is hydrogen and R₁, R₂ and R₃ are other than hydrogen and atleast two of them meet the prerequisite of the family, the dyes may beprepared by methods I or IV.

Where none of the R's are hydrogens, the dyes may be prepared by methodsII or III; the choice of method will depend on the value of n and thedegree of symmetry desired. When the value of n is to exceed 1, methodIII cannot be used. Method III has the advantage of giving any choice ofsymmetry from totally unsymmetrical to totally symmetrical, but thevalue of n is limited to 1.

Method I. Reaction of a p-aminophenyl alkene and a P-aminophyenl alkenealdehyde

Equimolar quantities of a p-aminophenyl alkene of the class ##STR253##(where R_(a) can equal H, aryl, alkyl, or arylamine groups) andp-aminophenyl alkene aldehyde of the class ##STR254## (where n=0,1) areallowed to react in a nonaqueous solvent with an acid catalyst such asacetic acid, or acetic anhydride, and the acid of the desired dye form.The reaction mixture is allowed to stand for 5 days at room temperature.This is poured into water and neutralized until the dye precipitates.The precipitate is filtered off, dried, and recrystallized fromanhydrous alcohol. This will produce a dye of the general-type formulaas depicted below: ##STR255##

Method II. Reaction of p-Aminophenyl alkene and an Orthoester MethodIIa. (for compounds having 5 or more methine carbon atoms)

Two molar proportions of a p-aminophenyl alkene of the class ##STR256##(where R_(o) can equal H, aryl, alkyl, or arylamine group) with one moldof an orthoester of the class ##STR257## (where m=O, 1, 2, or 3) areallowed to react in a nonaqueous solvent, containing an acid catalystsuch as acetic anhydride and the acid to form the desired carboniumcompound. The reaction mixture is allowed to stand at room temperaturefor several hours. Ether is added to precipitate the dye. Theprecipitate is filtered and washed with ether or an ether-polar solventmixture. The precipitate is dried in vacuum. This will produce acompound of the general-type formula as pictured below: ##STR258##(where n=0, 1, 2, 3, or 4).

Method IIb

By substituting tetramethyl ortho carbonate for the orthoester of methodIIa and by increasing the p-aminophenyl alkene to a molar proportion ofthree, a new type of compound was prepared, having the generalstructure: ##STR259## A nitrogen determination on ##STR260## using aColeman nitrogen analyzer found 8.58 percent nitrogen (theoretical8.61).

Method III. Reaction of a Ketone and a 1-(P-Aminophenyl)-1-(R) Alkene

A ketone of the general-type formula ##STR261## is refluxed with asubstituted alkene, of the general-type formula ##STR262## where R issomething other than hydrogen with phosphorous oxychloride as thesolvent catalyst. At the end of the reflux, the reaction mixture iscooled and poured into water and treated with a salt of the acid toyield the desired anion form of the dye. The aqueous mixture isneutralized with solid sodium acetate until the dye precipitates.

This method yields a dye of the general-type formula ##STR263## whereR_(a) and R_(b) may be equal or different.

Method IV. Reaction of a Ketone and a p-Aminophenyl Alkene

A ketone of the general-type formula ##STR264## is refluxed for 5 hourswith a substituted alkene of the general-type formula ##STR265## withphosphorous oxychloride as a solvent catalyst. At the end of the 5-hourreflux time, the reaction mixture is cooled and poured into water andtreated with a salt of the acid to yield the desired anion form of thedye. The aqueous mixture is neutralized with solid sodium acetate untildye precipitates.

This method yields a dye of the general-type formula: ##STR266## whereR_(a) and R_(b) may be equal or different.

Organic Synthesis Procedures

Method No. 1: Polymethine dyes

Example: Preparation of dye PP 2109

Step A: Preparation of p-Fluorobenzanilide ##STR267##

A solution of aniline, 23.7 g (0.255 mole) in 250 ml of dry ethercontaining 55.3 g of potassium carbonate was heated to refluxtemperature. To the refluxing mixture, 50 g (0.32 mole) ofp-fluorobenzoyl chloride was added over a period of one hour. Thereaction mixture was refluxed for four hours and the ether distilledoff. Cold water was added to the residue and the p-fluorobenzanilidecollected by filtration. Yield: 64 g, metling point 196° C., whitecrystalline powder.

Step B. Preparation of

p-N,N-Di-n-propylamin-p-fluorobenzophenone ##STR268## 64 g (0.3 mole) ofdry, powdered p-fluorobenzanilide, 100 g (0.6 mole) ofN,N-di-n-propylaniline, and 55 ml of phosphorous oxychloride were mixedin a 500 ml three-necked flask fitted with a stopper, a thermometer anda reflux condenser having a CaCl₂ drying tube on top. The reactionmixture was warmed gently until the temperature reached 100°-112° C., atwhich point an exothermic reaction occurred and the temperature rose to160° C. As soon as the exothermic reaction was noted, the mixture wasimmediately cooled by swirling the flask in ice water. The cooling wascontinued until the temperature dropped to 100°-105° C. This temperaturerange was held for three hours. The reaction mixture was then hydrolyzedin a three liter beaker by the addition of 58 ml concentratedhydrochloric acid in 445 ml water. The reaction mixture was allowed tostand for eight to twelve hours to complete the hydrolysis. Anadditional 4100 ml of water was then added to precipitate the ketoneformed. This was filtered, washed thoroughly with cold water, reslurriedand refiltered. Yield: 45 g, light green sandy crystals, melting point85°-87° C.

Step C: Preparation of1-(4-N,N-Di-n-propylamino-phenyl)-1-(4-fluorophenyl) ethylene ##STR269##

Sixty ml of a 3 molar etherial solution of methyl magnesium bromide wasevaporated almost to dryness under reduced pressure in a 500 mlthree-necked flask equipped with thermometer and nitrogen sparger. Thegrey moist residue was suspended in 75 ml of dry benzene. The flask wasthen equipped for refluxing by the addition of a condenser fitted with aCaCl₂ drying tube and an addition funnel. A 0.1 mole portion of theketone dissolved in 250 ml of boiling benzene was then placed in theaddition funnel and added dropwise to the warmed methyl magnesiumbromide-benzene slurry over a half-hour period. The resulting reddishsolution was refluxed for three hours. The termination of the reactionwas indicated by the fading of the initial reddish color to a paleyellow. The reaction mixture was then cooled to room temperature andcautiously treated with 45 ml of saturated ammonium chloride solution.This mixture was filtered and the filtrate boiled with 0.1 g ofp-toluenesulphonic acid until the evolution of water was completed. Theacid contained in the reaction mixture was then removed by the additionof 0.5 g of sodium bicarbonate. The volume was reduced to one half byevaporation under reduced pressure. Five hundred ml of dry ethanol wasadded to the remaining solution, which was then allowed to cool with thesubsequent precipitation of the ethylene compound.

The precipitate was filtered, washed with 50 ml ice cold ethanol, andthe crystals dried in a vacuum oven. Yield: 86 percent of theory:melting point 101°-102° C.

Step D: Preparation of a perchlorate of1,5-di-(p-fluorophenyl)-1,5-bis-(p-N,N-di-n-propylanilino)-1,3-pentadiene##STR270##

A mixture of 23.6 g (0.08 mole) of1(4-N,N-di-n-propylaminophenyl)-1-(4-fluorophenyl)ethylene, 12 ml ofethyl orthoformate and 50 ml of acetic anhydride was treated with anice-cold solution of 4 ml of 72 percent perchloric acid dissolved in 50ml of acetic anhydride. The resulting dark red solution was heated in awater bath at 85° C. for one hour, after which another 12 ml of ethylorthoformate was added. The mixture was than allowed to stand at roomtemperature for 18 hours to precipitate the condensation product. Theprecipitate was collected and washed with acetic acid, ethanol andether. Yield: 68 percent based on perchloric acid, golden brown crystalsmelting with decomposition at 277° C. Method No. 2: Polymethine dyesExample: Preparation of dye PP 2110 Step A: Preparation of3-Amino-4-methoxy-4'-N,N-Di-methylaminobenzophenone ##STR271##

Fifty grams (0.2 mole) of 3-amino-4-methoxybenzanilide, 70 g (0.58 mole)N,N-dimethylaniline and 36 g POCl₃ were heated on a water bath at 90° C.to 95° C. for 4 to 6 hours. The product was then cautiously poured intoa solution of 23 ml of concentrated hydrochloric acid in 250 ml water.The resulting solution was warmed at 80° C until the initial reddishcolor disappeared, indicating that the aniline was completelyhydrolyzed. A liter of water was added to precipitate the ketone, whichwas filtered, washed with cold water, and recrystallized from a 2:1aqueous alcohol solution. Yield: 38 g of slightly yellowish crystals,metling point 82° C.

Step B: Preparation of1(4-N,N-Dimethylaminophenyl)-1-(3-amino-4-methoxyphenyl)ethylene##STR272##

Fifty ml of a 3 M ethereal solution of methyl magnesium bromide wasevaporated almost to dryness under reduced pressure. Dry nitrogen wasadmitted to the reaction flask and the gray residue was suspended in 75ml of dry benzene. The slurry was warmed, then 26.6 g (0.1 mole) of theketone compound dissolved in 250 ml boiling benzene was added over a15-minute period. The resulting solution was refluxed until the paleyellow color faded to colorless (45 minutes). The mixture was cooled andtreated with 50 ml of a saturated NH₄ Cl solution. The colorlesssolution was filtered through a folded filter paper without applyingvacuum and in the absence of strong light. The filtrate was boiled with0.1 g p-teluenesulfonic acid until the evolution of water was complete.The cooled solution was neutralized by the addition of 0.2 g dry NaHCO₃and then reduced to 1/4volume by evaporating the solvent under reducedpressure. The remaining solution was diluted with 250 ml of dry ethanoland the ethylene product allowed to precipitate over 12 hours. Yield: 34percent of theory, yellow hygroscopic flakes, melting point 118° C.

Step C: Condensation Reaction Leading to Dye (A perchlorate of1,5-di-(3-amino-4-methoxyphenyl)-1,5-bis-(p-N,N-dimethylaniline)-1,3-pentadiene.A mixture of 26.9 g (0.1 mole) of1(4-N,N-di-methylaminophenyl)-1-(3-amino-4-methoxyphenyl)ethylene, 15 mlof ethyl orthoformate and 45 ml acetic anhydride was treated with asolution of 4 ml of 72 percent perchloric acid and 40 ml acetic acidpreviously cooled to 0° C. The resulting mixture was allowed to stand atroom temperature for 5 days, after which it was treated with 25 ml ofether and kept an additional day at room temperature. The precipitateformed was filtered and washed with acetic acid, ethanol, and ether, anddried in a vacuum dessicator.

Product: sandy crystals, dark brown, melting point 209°-210° C.

Note: The reaction should be run at room temperature. Condensation atelevated temperatures yields a black, insoluble polymerization product.##STR273##

APPENDIX III Azo Polymethines

Dyes of the general structural type ##STR274## are prepared bycondensation of p-aminophenyl alkene aldehydes or ketones withauramine-type hydrochlorides. One such dye was prepared: ##STR275##1,1,5-tris-4(N,N-dimenthyamino)phenyl-2-azo, pentene carbonium chloridewhich showed only very slight yellow phototropy.

APPENDIX IV Diazo Polymethines

A new type of dye, believed to have the general structures, ##STR276##was prepared by nitrosation of auramine-type structures ##STR277## withnitrous acid to yield ##STR278##

This is then reacted with p-aminophenyl alkenes to yield structures ofType A. Confirmation of structure is incomplete, but significant to thiswork is that the above series of reactons yield phototropic materials.

The position of the -N-N- group in the carbon chain may be changed tooccupy the 1 and 2 positions, as well as the above shown 2 and 3petitions, by using a secondary amine in place of B in the above seriesof reactions. With nitrogen atoms in the 1 and 2 positions, the 1position nitrogen becomes a quaternary ammonium atom in one of theresonance states of the molecule.

One dye of each of these types was prepared. Both were found tophototropic. They are: ##STR279## 1,1,5,5-tetrakis-4-(N,N-dimethylamino)phenyl!-2,3-diazo pentene carbonium (Code PP2031)##STR280## 1,1-bux-4-(N,N-dimethylamino)phenyl-3,4-bis-(phenyl)!-3,4-diazo butene carbonium(Code PP 2030)

APPENDIX V Quaternary Ammonium Salt Polymethines

Three dyes of the type ##STR281## were prepared and tested forphototropy. ##STR282## N-(p-dimethylamino cinnamylidine)-N,N-diphenylammonium proved to be phototropic but broke down rapidly underultraviolet light ##STR283## N-(p-dimethylaminocinnamylidine)-N,N-diethanol ammonium, and ##STR284## N-(p-dimethylamino cinnamylidine) N,N-di-4(N,N-dimethylamino)phenyl ammonium were notphototropic.

The dyes where prepared by the condensation of dimethylamino cinnamicaldehyde with the hydrochloride of secondary amines in warm, anhydrousalcohol according to the method of Brooker.

APPENDIX VI Intermediates

Although most types of dye intermediates are available, specificcompounds necessary to this work were not available on the commercialmarket. It was necessary to synthesize 13 such intermediates.

The syntehsis or type synthesis of these intermediates are for the mostpart given in standard works on synthesis dyes and dye intermediates.

The synthesis of tetramethyl orthocarbonate and ethylenes of the typeare reported herein.

Synthesis of Tetramethyl Ortho Carbonates

To 500 grams of cold dry methanol under reflux, 80 grams of metallicsodium in large pieces are added. (The alcohol solution has to be cooledexternally with ice water to prevent loss of methanol through the refluxcondenser.) Before all of the sodium has dissolved, 100 grams ofchloropicrin that has been diluted with 200 ml of methanol is slowlydropped in. The solution is refluxed for one hour. The methanol isdistilled off until the residue seems almost dry. This is then dissolvedin 600 cc of water, and the aqueous solution is extracted with three200-ml portions of ether. The composited ether extracts are dried overcalcium chloride. The ether is fractionated from the dried solution anda little sodium methoxide in methanol is added to the residue to reactwith any unreached chloropiorin. This is allowewd to stand overnight.The solution is fractionated, collecting one fraction between 110°-115°C. ##STR285##

Methyl magnesium bromide in ethyl ether is placed into a round bottomflask equipped with a condenser and an addition funnel. The ether isdistilled off, and the methyl magnesium bromide then taken up withanhydrous benzene. A ketone is dissolved in anhydrous benzene and addeddropwise to the Grignard reagent with continuous heating. After theaddition is completed, the mixture is refluxed for three more hours.After cooling, sufficient ammonium chloride solution (saturated aqueoussolution) is very carefully added in order to dissolve any freemagnesium. The Grignard complex is decomposed with hydrochloric acid.After decomposition of the complex is complete, the solution is allowedto come to room temperature. After making sure the solution is alkalineto phenolphthalein, the benzene solution is decanted off of the solids.The solids are washed with two 50-ml positions of ether and the washingscombined with the benzene solution. The ether-benzene solution is driedover anhydrous sodium sulfate.

The ether and benzene are then distilled off leaving a residue. Thisresidue is vacuum-distilled at 2-5 mm of Hg.

APPENDIX VII

Method No. 3: Indoline base dyes Example: Preparation of dye PP 1210Step A: Synthesis of p- N-(2-chloroethyl)-N-ethyl!aminobenzaldehyde##STR286##

At 50° C. 82.5 parts by weight of N-(2-hydroxyehtyl)-N-ethylaniline wereadded dropwise to 90 parts by weight of phosphorous oxychloride. Thesolution was then heated at 90° C. for 6 hours. After colling to 0° C.,a mixture of 150 parts by weight of N-methylformanilide, 170 parts byweight of phosphorus oxychloride, and 120 parts by weight of benzene wasadded to the above solution. The mixture was heated for a few hours at30°-35° C. After neutralization with an aqueous solution of sodiumhydroxide, the benzene solution of the aldehyde product was separated.After evaporating the benzene, p-N-chloroethyl-N-ethylamino benzaldhyderemained as a slightly yellow oil which hardened on standing and couldbe recrystallized from ethanol. The recrystallized aldehyde had a whiteflaky appearance and a melting point of 283° C.

Step B: Synthesis of dye PP 2120, Chloride of 2,3,3-trimethyl-2-p-(N-2-chloroethyl-N-ethyl)amino-β-s tyryl! indoline. ##STR287##

p-(N-Chloroethyl-N-ethyl)amino benzaldehyde (12.5 parts by weight) wasrefluxed for 6 hours at 100° C. with 8.5 parts by weight of1,3,3-trimethyl-2-methlyene-indoline in 60 parts by weight of glacialacetic acid. The mixture was then poured into water and the condensationproduct was salted out with sodium chloride. The crude dyestuff wasobtained as a dark bronze resinous liquid which hardened upon standingand could be crushed into shiny bronze particles. The pure dye wasobtained by recrystallization from hot water, m.p. 167°-168° C.

APPENDIX VIII Method No. 4: Dyes with more than one chromophore Example:Preparation of dye PP 2131 Step A: Synthesis ofphenetolazobenzaldehydsulphonic acid

One hundred grams of Chrysophenin G concentrate, which was equivalent toabout 92 grams of the pure compound, was dissolved in 6 liters ofboiling water. The solution was cooled to 0°-5° C. by the addition ofice and then saturated with sodium chloride. ##STR288##

A 3 percent solution of potassium permanganate was slowly added withvigorous agitation until a pale pink color persisted. (The quantity ofpermanganate required was 29 grams.) The precipitate which formed duringthe reaction was allowed to settle and was collected by siphoning offthe supernatant liquor. The product was isolated by boiling theprecipitate two or three times with one liter of water, filtering offthe manganese dioxide and adding potassium chloride to the hot watersolution until precipitation was complete. An additional small quantityof aldehyde was isolated by salting it out of the supernatant liquorwith potassium chloride. The product precipitated from water inorange-colored microscopic needles.

Step B: Synthesis of Dye PP 2131, perchlorate of1,1-bis-(p-N,N-dimethylamino)phenyl-3- 2-sulfonato-4-(p-ethoxyphenylazoo! phenyl propene.

Phenetoleazobenzaldehyde sulphonic acid (1.86 parts by weight) wasrefluxed for 6 hours at 100° C. with 1.33 parts by weight of1,1-bis-(4-N,N-dimethylamino)phenyl ethylene is 25 parts by weight ofglacial acetic acid. The condensation product was then poured into waterand salted out. The dyestuff was obtained as a thick dark green liquidwhich hardened upon standing to a crushable solid, melting point 78°-92°C. An attempt to recrystallize the dye using a variety of solvents wasunsuccessful.

APPENDIX IX Example 1 - Xylene Blue VS cyanide

To a solution of 25 g. of commercial Xylene Blue VS, Colour Index No.672, in 150 ml. of water is added 4.5 g. of 95% sodium cyanide and themixture is heated in a pressure bottle for 1 hour. Suitable precautionsshould be taken to avoid cuts by glass wet with sodium cyanide solutionin the event of the explosion of the bottle. The solution is thencooled, allowed to stand for 1 day at 25° C. and filtered from theprecipitated Xylene Blue VS cyanide disodium salt having the formula##STR289##

The disodium salt is readily soluble in water to yield a colorlesssolution that slowly becomes blue on exposure to radiation of wavelength 2537 A. The color change is much slower than with a solution of arepresentative basic dye cyanide, such as malachite green syanide inalcohol, and thus is useful in the actinometry of more intenseradiation.

The free acid form of Xylene Blue VS cyanide, having the formula##STR290## may be prepared by treatment of a solution of 11 g. of thedisodium salt in 100 ml. of water with 11.2 ml. of concentratedhydrochloric acid. After the mixture has stood at room temperature for 2days, the colorless precipitated from acid is collected on a filter,washed with water, and air dried. It is sparingly soluble in water. Adilute, colorless, aqueous solution of the free acid color blue onultra-violet irradiation at a speed intermediate between that of thesolutions of the sodium salt and of alcoholic solutions of malachitegreen cyanide.

The barium salt of Xylene Blue VS cyanide having the formula ##STR291##may be prepared by neutralization of a hot 1/2of 1% aqueous solution ofthe free acid to pH 3.4 with N10 barium hydroxide solution. Theneutralized solution is cooled to room temperature, allowed to stand for3 days, and filtered from the colorless, crystalline barium salt. Thebarium salt is less soluble in water than the free acid, but quitesufficiently soluble to give photosensitive solutions that behave onexposure to ultra-violet like solutions of the sodium salt.

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What is claimed is:
 1. A chemical compound having the formula A-B-C,whereA is a chemiluminescent moiety which reacts with peroxides andoxygen free radicals and is capable of transferring energy from its ownexcited state to B; B is a photochromic moiety covalently bonded to Awhich receives energy from A to achieve an excited state, wherein theemission spectrum of A overlaps the absorption-release reaction spectrumof B in the wavelength range of 250 nm to 420 nm; and C is abiologically active agent covalently bonded to B, wherein relaxation ofthe excited state of B causes heterolytic cleavage of the covalent bondbetween B and C, thereby releasing C from B.
 2. The chemical compound ofclaim 1, wherein said chemiluminescent moiety is a lophine, anacridinium ester, an acridan, a tetraphenylpyrrole, a phthalhydrazide,an acyloin, a biacridinium salt, a vinylcarbonyl, a vinylnitrile, anacylperoxide, an indole, a tetracarbazole, an active oxalate,2,6-diaminopyrene, a dioxetan, a dioxetanone, an imidazole, asulfonyloxamide, a tetrakis (dialkylamino) ethylene,2,5,7,8-tetraoxabicyclo- 4.2.0.!octane, a lucigenin, a diphenylperoxide, or a dioxene.
 3. The chemical compound of claim 1, whereinsaid photochromic moiety comprises a cationic dye which demonstratesphotochromic behavior with electromagnetic radiation and bleachingagents.
 4. The chemical compound of claim 3, wherein said cationic dyeis a di or triarylmethane dye, a triarylmethane lactone or a cyclicether dye, a cationic indole, a pyronine, a phthalein, an oxazine, athiazine, an acridine, a phenazine, an anthocyanidin, a cationicpolymethine dye, an azo or a diazopolymethine, a styryl, a cyanine, ahemicyanine, or a dialkylaminopolyene.
 5. A chemical compound having theformula A-B-C, whereA is a chemiluminescent moiety which undergoes anoxidation reduction reaction and is capable of transferring energy fromits own excited state to B; B is a photochromic moiety covalently bondedto A which receives energy from A to achieve an excited state, whereinthe emission spectrum of A overlaps the absorption-release reactionspectrum of B in the wavelength range of 250 nm to 420 rnm; and C is abiologically active agent covalently bonded to B, wherein relaxation ofthe excited state of B causes heterolytic cleavage of the covalent bondbetween B and C, thereby releasing C from B.
 6. The chemical compound ofclaim 5, wherein said chemiluminescent moiety is a cation radical or aruthenium chelate.
 7. The chemical compound of claim 5, wherein saidchemiluminescent moiety is selected from the group consisting oftris-2,2'-bipyridinedichlororuthenium (11) and 2 6-diaminopyrene.
 8. Achemical compound having the formula A-B-C, whereA is a phthalhydrazidecapable of transferring energy from its own excited state to B; B is apolymethine dye covalently bonded to A which receives energy from A toachieve an excited state, wherein the emission spectrum of A overlapsthe absorption-release reaction spectrum of B in the wavelength range of250 nm to 420 nm; and C is a biologically active agent covalently bondedto B, wherein relaxation of the excited state of B causes heterolyticcleavage of the covalent bond between B and C, thereby releasing C fromB.
 9. The chemical compound of claim 8, wherein C is selected from thegroup consisting of 3,5-diiodo-4-hydroxybenzoic acid, y-aminobutyricacid, gabaculine, N-5'-phosphopyridoxyl-4-aminobutyric acid, baclofen,trans-4-aminocrotonic acid, compactin,3-hydrox-3-methylglutarate!3-hydroxy-3-methylglutarate,p-glycolohydroxamate, N-(phosphonoacetyl)-L-aspartate, phosphonoacetate,mimosine, 2-mercaptoethylamine, NSD
 1055. polvoxin DD,L-hydrazino-α-methyldopa, and phosphonoformate.
 10. The chemicalcompound of claim 1, wherein C is a drug molecule which effects atherapeutic functional change by a mechanism selected from the groupconsisting of receptor mediated mechanisms and nonreceptor mediatedmechanisms.
 11. The chemical compound of claim 1, wherein C is selectedfrom the group consisting of antilipidemic drugs, anticholesterol drugs,anticoagulants, antihypertensive drugs, cardiac inotropic drugs,antineoplastic drugs, antidepressant drugs, agents for the treatment ofasthma and hypersensitivity reactions, diuretics, antifungal agents,antibacterial drugs, anxiolytic agents, sedatives, muscle relaxants,anticonvulsants, agents for the treatment of ischemic heart disease,agents which activate the effects of secondary messengers, agents toblock spinal reflexes, and antiviral agents.
 12. The chemical compoundof claim 1, wherein C is an antihypertensive agent.
 13. The chemicalcompound of claim 12, wherein C is selected from the group consisting of3,5-diiodo-4-hydroxybenzoic acid, mimosine, D,L-hydrazino-(I-methyldopa,and 2-mercaptoethylamine.
 14. The chemical compound of claim 1, whereinC is an antiviral agent.
 15. The chemical compound of claim 14, whereinC is selected from the group consisting of phosphonoacetate andphosphonoformate.
 16. The chemical compound of claim 1, wherein C is ananticholesterol agent.
 17. The chemical compound of claim 16, wherein Cis selected from the group consisting of compactin and3-hydroxy-3-methylglutarate.
 18. The chemical compound of claim 1,wherein C is an anticonvulsant agent.
 19. The chemical compound of claim18, wherein C is selected from the group consisting of gabaculine,N-5'-phosphopyridoxyl-4-aminobutyric acid, baclofen,trans-4-aminocrotonic acid, and 7-aminobutyric acid.
 20. The chemicalcompound of claim 1, wherein C is an antibacterial or antifungal agent.21. The chemical compound of claim 20, wherein C is selected from thegroup consisting of p-glycolohydroxamate and polyoxin D.
 22. Thechemical compound of claim 1, wherein C is an antineoplastic agent. 23.The chemical compound of claim 22, wherein C isN-(phosphonoacetyl)-L-aspartate.
 24. The chemical compound of claim 1,wherein the chemical compound is covalently bound to a biocompatiblepolymer to which an enzyme is immobilized.
 25. The chemical compound ofclaim 24, wherein C is insulin and the enzyme is glucose oxidase. 26.The chemical compound of claim 24, wherein C is tissue plasminogenactivator and the enzyme is xanthine oxidase.